Method of treating cancers and a pharmaceutical composition that may be used in  practicing said method

ABSTRACT

The method of treating a person having a cancer selected from carcinoma, sarcoma or hematopoietic cancer by administering (a) an effective amount of at least one anti-cancer drug selected from the group consisting of an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor receptor (VEGFR) inhibitor and a Raf kinase inhibitor and (b) an effective amount of 5-(4-(6-(4-amino-3,5-dimethyl-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride provided that said carcinoma is not lung cancer when an EGFR inhibitor is erlotinib. The invention also provides a pharmaceutical composition that may be used in practicing said method.

This application is a continuation application of Ser. No. 12/221,019filed Jul. 30, 2008 which is a continuation-in-part application ofinternational application PCT/JP2007/052178 filed Feb. 8, 2007.

TECHNICAL FIELD

The present invention relates to (a) an anti-cancer pharmaceuticalcomposition which contains a thiazolidinedione compound having aperoxisome proliferators activated receptor (PPAR)γ activation potencyas an active ingredient, and to (b) an anti-cancer pharmaceuticalcomposition for prophylaxis or treatment of carcinoma, sarcoma orhematopoietic cancer which contains (i) a compound having a PPARγactivation potency and (ii) an epidermal growth factor receptor (EGFR)inhibitor, a vascular endothelial growth factor receptor (VEGFR)inhibitor or a Raf kinase inhibitor as active ingredients.

The present invention also relates to a method of treating a personhaving specified cancers by administering to said person athiazolidinedione compound having a peroxisome proliferators activatedreceptor (PPAR)γ activation potency. The present invention furtherrelates to a method for the prophylaxis or treatment of a person havinga carcinoma, sarcoma or hematopoietic cancer by administering to saidperson (i) a compound having a PPARγ activation potency and (ii) atleast one drug selected from epidermal growth factor receptor (EGFR)inhibitor, a vascular endothelial growth factor receptor (VEGFR)inhibitor or a Raf kinase inhibitor.

BACKGROUND ART

It is widely known that PPARγ activators are useful as therapeutic drugsfor type 2 diabetes mellitus, as seen in examples such as rosiglitazoneand pioglitazone. PPARγ is considered to have various physiologicalfunctions such as inducement of differentiation into adipocytes andadjustment of biogenic energy metabolism (for example, refer toNon-patent Documents 1 and 2). On the other hand, it has been reportedthat PPARγ activators induce differentiation, cell cycle inhibition orapotosis against certain types of cancer cells, and cause growthinhibition of cancer cells (for example, refer to Non-patent Documents3, 4 and 5). In addition to these findings, since chromosomaltranslocation of PAX8-PPARγ has been frequently observed and thefunction of PPARγ is inactivated in thyroid cancer, and since a pointmutation which causes dysfunction, though not high in frequency, isobserved in colon cancer, it has been suggested that PPARγ acts in aninhibitory manner against oncogenic transformation (for example, referto Patent Documents 6 and 7). From these findings, the possibility ofPPARγ activator potency for treating cancer has been considered, andsmall clinical tests have been conducted with cancer patients by usingrosiglitazone. However, sufficient efficiency was not observed (forexample, refer to Patent Document 8). Thus far, the reason for thisresult has not been discovered; however, it is highly likely that theanti-cancer effect by rosiglitazone was not strong enough. Accordingly,finding a PPARγ activator which has a stronger anti-cancer effect isexpected to contribute greatly to the treatment of cancer in future.

On the other hand, in recent cancer treatments, an approach in which aplurality of anti-cancer drugs are used in combination to increase theefficiency of the drugs and to reduce side effects, compared with thecase where each of the drugs is administered separately, has beenattempted. As types of anti-cancer drugs used in combination treatment,cytocidal cancer chemotherapy drugs and various molecular target drugsthat have been newly introduced to the market recently, can bementioned. In particular, molecular target drugs are generally low inside effects compared with the former, and it is often the case thatthere is no need to decrease the usage amount of the former to preventside effects from increasing, with respect to combinationadministration. Therefore, in combination therapy, since the efficiencyof cytocidal cancer chemotherapy drugs can be obtained to the maximumand since their effect can be enhanced by the drug efficacy of moleculartarget drugs, development of various drugs that target molecules isconducted extensively at present. Examples of molecular target drugswhich are presently gaining attention are bevacizumab (product nameAvastin) which is an antibody medicament having anti-angiogenesisactivity, and gefitinib (product name Iressa) and erlotinib (productname Tarceva), which are epidermal growth factor receptor (EGFR)inhibitors. In addition, sorafenib, which has anti-angiogenesis(vascular endothelial growth factor receptor (VEGFR) inhibitory)activity in combination with Raf kinase inhibitory activity and ispresently in the stage of clinical testing, is also suggested to haveefficiency in clinical tests and is gaining attention. As described, theindication that anti-cancer effects can be enhanced by combinationadministration with these molecular target drugs enables varioustreatment options to be provided to a patient when considering a cancertreatment, and thus greatly contributes to improvement in treatmentoutcome. Here, the enhancement of anti-cancer efficiency by combinationadministration generally indicates that the efficiency obtained bycombination administration is superior to the efficiency obtained bysingle administration of each drug (for example, refer to Non-patentDocument 9), and the clinical significance is considered to be largeeven when a synergistic enhancing effect cannot be obtained.

Japanese Patent No. 3488099 (for others, refer to Patent Documents 1 and2) discloses a thiazolidinedione compound having a novel chemicalstructure. A compound represented by the general formula (I), which iscontained as an active ingredient of the anti-cancer pharmaceuticalcomposition according to the present invention, is a compound which isembraced in the scope of compounds relating to the thiazolidinedionecompound disclosed in the patent. Japanese Patent No. 3488099 disclosesthat the thiazolidinedione compound disclosed in the published patenthas PPARγ activation potency and can be used as an anti-cancer drug.However, the patent does not disclose any specific test data which showsthat the thiazolidinedione compound actually has an anti-cancer action.

Further, pharmaceutical compositions which contain thisthiazolidinedione compound and another drug have been reported.

For example, a pharmaceutical composition containing thisthiazolidinedione compound and a MAP kinase inhibitor has been reported(refer to Patent Documents 3 and 4), and it is disclosed that thispharmaceutical composition is useful as a preventive drug, a therapeuticdrug or as a cell proliferation inhibitor of cancer such as gastriccancer, lung cancer, breast cancer, colon cancer, prostate cancer,pancreatic cancer, liver cancer, leukemia, head and neck cancer orliposarcoma.

In addition, a pharmaceutical composition for prophylaxis or treatmentof cancer which contains some of the compounds included in the scope ofcompounds relating to the aforementioned thiazolidinedione compound anda RXR (retinoid X receptor) activator has been reported (refer to PatentDocuments 5 and 6), and it is disclosed that this pharmaceuticalcomposition is useful as a therapeutic drug or as a preventive drug forespecially lung cancer, gastric cancer or colon cancer.

A pharmaceutical composition containing the aforementionedthiazolidinedione compound and a fluorouracil type antimetabolite or aplatinum complex has been reported (refer to Patent Documents 7 and 8),and it is disclosed that this pharmaceutical composition is usefulespecially as a preventive drug, a therapeutic drug or as a cellproliferation inhibitor of cancer such as gastric cancer, lung cancer,breast cancer, colon cancer, prostate cancer, pancreatic cancer, livercancer, leukemia, head and neck cancer or liposarcoma.

A pharmaceutical composition containing the aforementionedthiazolidinedione compound and a diuretic drug has been reported (referto Patent Documents 9 and 10), and it is disclosed that thispharmaceutical composition can prevent or treat side effects that arecaused when PPARγ activator is administered, such as hypercardia, edema,fluid retention, and pleural effusion retention, and is usefulespecially as a preventive drug, a therapeutic drug or as a cellproliferation inhibitor of cancer such as gastric cancer, lung cancer,breast cancer, colon cancer, prostate cancer, pancreatic cancer, livercancer, leukemia, head and neck cancer or liposarcoma.

A pharmaceutical composition containing the aforementionedthiazolidinedione compound and a novel sulfamide compound having MEKinhibitory activity has been reported (refer to Patent Documents 11 and12), and it is disclosed that this pharmaceutical composition is usefulespecially as a preventive drug, a therapeutic drug or as a cellproliferation inhibitor of cancer such as gastric cancer, lung cancer,breast cancer, colon cancer, prostate cancer, pancreatic cancer, livercancer, leukemia, head and neck cancer or liposarcoma.

-   [Patent Document 1] U.S. Pat. No. 6,432,993-   [Patent Document 2] EP Patent No. 1022272-   [Patent Document 3] Japanese Patent Application (Kokai) No.    2003-192592-   [Patent Document 4] Pamphlet of International Publication No. WO    03/032988-   [Patent Document 5] Japanese Patent Application (Kokai) No.    2003-238406-   [Patent Document 6] Pamphlet of International Publication No. WO    03/053440-   [Patent Document 7] Japanese Patent Application (Kokai) No.    2004-83558-   [Patent Document 8] Pamphlet of International Publication No. WO    03/082865-   [Patent Document 9] Japanese Patent Application (Kokai) No.    2004-83574-   [Patent Document 10] Pamphlet of International Publication No, WO    2004/000356-   [Patent Document 11] Japanese Patent Application (Kokai) No.    2005-162727-   [Patent Document 12] Pamphlet of International Publication No. WO    2004/083167-   [Non-patent Document 1] Spiegelman B M. PPAR-γ: Adipogenic regulator    and thiazolidinedione receptor. Diabetes, 1998; 47: 507-14.-   [Non-patent Document 2] Lehmann J M, Moore L B et al. An    antidiabetic thiazolidinedione is a high affinity ligand for    peroxisome proliferator-activated receptor gamma. J Biol Chem 1995;    270: 12953-6.-   [Non-patent Document 3] Mueller E, Sarraf P et al. Terminal    differentiation of the human breast cancer through PPAR gamma. Mol    Cell 1998; 1: 465-70.-   [Non-patent Document 4] Yoshizume T, Ohta T et al.    Thiazolidinedione, a peroxisome proliferator-activated receptor    gamma ligand, inhibits growth and metastasis of HT-29 human colon    cancer cells through differentiation-promoting effects. Int J Oncol    2004; 25: 631-9.-   [Non-patent Document 5] Ray D M, Bernstein S H et al. Human multiple    myeloma cells express peroxisome proliferator-activated receptor γ    and undergo apoptosis upon exposure to PPARγ ligands. Clin    Immunology, 2004; 113: 203-13.-   [Non-patent Document 6] Dwight T, Thoppe S R, et al. Involvement of    the PAX8/peroxisome proliferator-activated receptor gamma    rearrangement in follicular thyroid tumors. J Clin Endocrinol Metab    2003; 88: 4440-5.-   [Non-patent Document 7] Sarraf P, Mueller E et al. Loss-of-function    mutations in PPAR gamma associated with human colon cancer. Mol Cell    1999; 3: 799-804.-   [Non-patent Document 8] Debrock G, Vanhentenrijk V et al. A phase II    trial with rosiglitazone in liposarcoma patients. Br J Cancer 2003;    89: 1409-12.-   [Non-patent Document 9] Tatsuo Saito ed., Development of Drug    Therapy for Cancer and Evaluation of Efficiency, Realize inc., pp.    128-138 (1985).

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

Accordingly, the inventors of the present invention have selected acompound represented by the general formula (I), which is an activeingredient of the anti-cancer pharmaceutical composition of the presentinvention, from the compounds that are within the scope of theaforementioned thiazolidinedione compound, and studied the anti-cancereffects of the compound represented by the general formula (I) accordingto the present invention, when the compound was used alone.

As a result, it has been found that the compound represented by thegeneral formula (I) or a pharmacologically acceptable salt thereofaccording to the present invention has superior anti-cancer effectagainst a particular type of cancer.

As a result of conducting extensive studies to find a combination ofdrugs having further superior anti-cancer action, the inventors of thepresent invention found that by administering a compound having PPARγactivation potency (especially a compound represented by the generalformula (I) of the present invention) or a pharmacologically acceptablesalt thereof, in combination with an epidermal growth factor receptor(EGFR) inhibitor, a vascular endothelial growth factor receptor (VEGFR)inhibitor, or a Raf kinase inhibitor, anti-cancer effects can beenhanced more than the case where they were each administeredseparately, and thereby completed the present invention.

Means for Solving the Problems

That is, the present invention is,

(1) an anti-cancer pharmaceutical composition for prophylaxis ortreatment of gastric cancer, colon cancer, lung cancer, breast cancer,pancreatic cancer, kidney cancer, prostate cancer, medulloblastoma,rhabdomyosarcoma, Ewing's sarcoma, liposarcoma, multiple myeloma orleukemia, comprising a compound represented by the following generalformula (I):

wherein,

R represents a phenyl group substituted with 1 to 5 groups selected fromSubstituent group α, and

X represents an oxygen atom or a sulfur atom.

-   <Substituent group α>: a halogen atom, a hydroxy group, a C₁-C₆    alkyl group, a halogeno C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, a    C₁-C₆ alkylthio group, an amino group which may be substituted with    1 or 2 groups selected from Substituent group γ, a C₃-C₁₀    cycloalkyl, C₆-C₁₀ aryl, C₇-C₁₆ aralkyl, C₆-C₁₀ aryloxy, C₇-C₁₆    aralkyloxy or C₆-C₁₀ arylthio group which may be substituted with 1    to 3 groups selected from Substituent group β, a C₁-C₇ aliphatic    acyloxy group, a 4- to 7-membered saturated heterocyclic group    containing nitrogen atom(s), a 5- or 6-membered aromatic    heterocyclic group containing nitrogen atom(s), a nitro group, and a    cyano group;-   <Substituent group β>: a halogen atom, a hydroxy group, a C₁-C₆    alkyl group, a halogeno C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, an    amino group which may be substituted with 1 or 2 groups selected    from Substituent group γ, a C₆-C₁₀ aryl group, and a nitro group;-   <Substituent group γ>: a C_(l)-C₁₀ alkyl group, a C₆-C₁₀ aryl group,    a C₇-C₁₆ aralkyl group, a C₁-C₇ aliphatic acyl group, a C₇-C₁₁    aromatic acyl group, a C₈-C₁₂ aromatic-aliphatic acyl group, a    C₄-C₁₁ cycloalkylcarbonyl group, and a 5- or 6-membered aromatic    heterocyclic carbonyl group containing nitrogen atom(s)], or a    pharmacologically acceptable salt thereof, as an active ingredient,

(2) the pharmaceutical composition according to the aforementioned (1),wherein

R represents a phenyl group substituted with 1 to 5 groups selected fromSubstituent group α, and

Substituent group a is the group consisting of a halogen atom, a C₁-C₆alkyl group, a halogeno C₁-C₆ alkyl group, an amino group which may besubstituted with 1 or 2 groups selected from Substituent group γ, a 4-to 7-membered saturated heterocyclic group containing nitrogen atom(s),and a 5- or 6-membered aromatic heterocyclic group containing nitrogenatom(s),

(3) the pharmaceutical composition according to the aforementioned (1),wherein R is a phenyl group substituted with one amino group which maybe substituted with 1 or 2 substituents (the substituents may be thesame or different, and each is a group selected from the groupconsisting of a C₁-C₁₀ alkyl group, a C₆-C₁₀ aryl group and a C₇-C₁₆aralkyl group), and may be further substituted with 1 to 3 substituents(each substituent is a group selected from the group consisting of ahalogen atom, a C₁-C₆ alkyl group, and a halogeno C₁-C₆ alkyl group),

(4) the pharmaceutical composition according to the aforementioned (1),wherein R is a phenyl group substituted with an amino or mono- ordi-C₁-C₁₀ alkylamino group, and may be further substituted with 1 or 2C₁-C₆ alkyl groups,

(5) the pharmaceutical composition according to any one of theaforementioned (1) to (4), wherein X is an oxygen atom,

(6) the pharmaceutical composition according to the aforementioned (1),wherein the compound represented by the general formula (I) is acompound selected from the following:

5-(4-(6-(3-isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,

5-(4-(6-(3-(isobutyl-methyl-amino)-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,

5-(4-(6-(4-(isobutyl-methyl-amino)-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,

5-(4-(6-(3-(ethyl-isopropyl-amino)-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,

5-(4-(6-(4-isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,

5-(4-(6-(4-sec-butylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,

5-(4-(6-(4-isobutylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,and

5-(4-(6-(4-amino-3,5-dimethyl-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,

(7) the pharmaceutical composition according to the aforementioned (1),wherein the compound represented by the general formula (I) orpharmacologically acceptable salt thereof is5-(4-(6-(4-amino-3,5-dimethyl-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride,

(8) the pharmaceutical composition according to the aforementioned (1),wherein the compound represented by the general formula (I) orpharmacologically acceptable salt thereof is5-(4-(6-(3-isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride,

(9) an anti-cancer pharmaceutical composition for prophylaxis ortreatment of carcinoma, sarcoma or hematopoietic cancer, comprising:

at least one anti-cancer drug selected from the group consisting of anepidermal growth factor receptor (EGFR) inhibitor, a vascularendothelial growth factor receptor (VEGFR) inhibitor and a Raf kinaseinhibitor; and

at least one compound selected from the group consisting of chemicalcompounds represented by the following general formula (I):

wherein

R represents a phenyl group substituted with 1 to 5 groups selected fromSubstituent group α; and

X represents an oxygen atom or a sulfur atom;

-   <Substituent group α>: a halogen atom, a hydroxy group, a C₁-C₆    alkyl group, a halogeno C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, a    C₁-C₆ alkylthio group, an amino group which may be substituted with    1 or 2 groups selected from Substituent group γ, a C₃-C₁₀    cycloalkyl, C₆-C₁₀ aryl, C₇-C₁₆ aralkyl, C₆-C₁₀ aryloxy, C₇-C₁₆    aralkyloxy or C₆-C₁₀ arylthio group which may be substituted with 1    to 3 groups selected from Substituent group β, a C₁-C₇ aliphatic    acyloxy group, a 4- to 7-membered saturated heterocyclic group    containing nitrogen atom(s), a 5- or 6-membered aromatic    heterocyclic group containing nitrogen atom(s), a nitro group, and a    cyano group,-   <Substituent group β>: a halogen atom, a hydroxy group, a C₁-C₆    alkyl group, a halogeno C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, an    amino group which may be substituted with 1 or 2 groups selected    from Substituent group γ, a C₆-C₁₀ aryl group, and a nitro group;-   <Substituent group γ>: a C₁-C₁₀ alkyl group, a C₆-C₁₀ aryl group, a    C₇-C₁₆ aralkyl group, a C₁-C₇ aliphatic acyl group, a C₇-C₁₁    aromatic acyl group, a C₈-C₁₂ aromatic-aliphatic acyl group, a    C₄-C₁₁ cycloalkylcarbonyl group and a 5- or 6-membered aromatic    heterocyclic carbonyl group containing nitrogen atom(s)], or a    pharmacologically acceptable salt thereof, as active ingredients,    wherein the active ingredients are for administering simultaneously    or separately at different times,

(10) the pharmaceutical composition according to the aforementioned (9),wherein the anti-cancer drug is at least one selected from the groupconsisting of an epidermal growth factor receptor (EGFR) inhibitor (thedrug being cetuximab, panitumumab, gefitinib, erlotinib or lapatinib), avascular endothelial growth factor receptor (VEGFR) inhibitor (the drugbeing bevacizumab, sorafenib, SU11248 or vatalanib) and a Raf kinaseinhibitor (the drug being sorafenib),

(11) the pharmaceutical composition according to the aforementioned (9),wherein the anti-cancer drug is at least one selected from the groupconsisting of gefitinib and sorafenib,

(12) the pharmaceutical composition according to any one of theaforementioned (9) to (11), wherein the carcinoma is gastric cancer,colon cancer, lung cancer, breast cancer, pancreatic cancer, kidneycancer or prostate cancer,

(13) the pharmaceutical composition according to any one of theaforementioned (9) to (12), wherein the sarcoma is medulloblastoma,rhabdomyosarcoma, Ewing's sarcoma or liposarcoma,

(14) the pharmaceutical composition according to any one of theaforementioned (9) to (13), wherein the hematopoietic cancer is multiplemyeloma or leukemia,

(15) the pharmaceutical composition according to any one of theaforementioned (9) to (14), wherein

R represents a phenyl group substituted with 1 to 5 groups selected fromSubstituent group α, and

Substituent group α is the group consisting of a halogen atom, a C₁-C₆alkyl group, a halogeno C₁-C₆ alkyl group, an amino group which may besubstituted with 1 or 2 groups selected from Substituent group γ, a 4-to 7-membered saturated heterocyclic group containing nitrogen atom(s),and a 5- or 6-membered aromatic heterocyclic group containing nitrogenatom(s),

(16) the pharmaceutical composition according to any one of theaforementioned (9) to (14), wherein R is a phenyl group substituted withone amino group which may be substituted with 1 or 2 substituents (thesubstituents may be the same or different, and each is a group selectedfrom the group consisting of a C₁-C₁₀ alkyl group, a C₆-C₁₀ aryl groupand C₇-C₁₆ aralkyl group), and may be further substituted with 1 to 3substituents (each substituent is a group selected from the groupconsisting of a halogen atom, a C₁-C₆ alkyl group and a halogeno C₁-C₅alkyl group),

(17) the pharmaceutical composition according to any one of theaforementioned (9) to (14), wherein R is a phenyl group substituted withan amino or mono- or di-C₁-C₁₀ alkylamino group, and may be furthersubstituted with 1 or 2 C₁-C₆ alkyl groups,

(18) the pharmaceutical composition according to any one of theaforementioned (9) to (17), wherein X is an oxygen atom,

(19) the pharmaceutical composition according to the aforementioned (9),wherein the compound represented by the general formula (I) is acompound selected from the following:

5-(4-(6-(3-isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,

5-(4-(6-(3-(isobutyl-methyl-amino)-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,

5-(4-(6-(4-(isobutyl-methyl-amino)-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,

5-(4-(6-(3-(ethyl-isopropyl-amino)-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,

5-(4-(6-(4-isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,

5-(4-(6-(4-sec-butylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,

5-(4-(6-(4-isobutylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,and

5-(4-(6-(4-amino-3,5-dimethyl-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,

(20) the pharmaceutical composition according to the aforementioned (9),wherein at least one compound selected from the group consisting of thecompounds represented by the general formula (I) or pharmacologicallyacceptable salt thereof is5-(4-(6-(4-amino-3,5-dimethyl-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride,and

(21) the pharmaceutical composition according to the aforementioned (9),wherein the compound selected from the group consisting of the compoundrepresented by the general formula (I) or pharmacologically acceptablesalt thereof is5-(4-(6-(3-isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride.

In addition, the present invention provides a method for prophylaxis ortreatment of gastric cancer, colon cancer, lung cancer, breast cancer,pancreatic cancer, kidney cancer, prostate cancer, medulloblastoma,rhabdomyosarcoma, Ewing's sarcoma, liposarcoma, multiple myeloma orleukemia, which comprises administration of the pharmaceuticalcomposition described in any one selected from the aforementioned (1)through (8) to a warm-blooded animal (preferably a human).

Further, the present invention provides a method for prophylaxis ortreatment of carcinoma (especially, gastric cancer, colon cancer, lungcancer, breast cancer, pancreatic cancer, kidney cancer or prostatecancer), sarcoma (especially, medulloblastoma, rhabdomyosarcoma, Ewing'ssarcoma or liposarcoma) or hematopoietic cancer (especially, multiplemyeloma or leukemia), which comprises administering the activeingredients of the pharmaceutical composition simultaneously oradministering each of the active ingredients at different times, theactive ingredients being as described in one selected from theaforementioned (9) through (21).

In the present invention, “halogen atom” in the definition ofSubstituent groups α and β is a fluorine atom, chlorine atom, bromineatom or iodine atom, preferably a fluorine atom or chlorine atom, andmore preferably a fluorine atom.

“C₁-C₆ alkyl group” in the definition of Substituent groups α and βrepresents a linear or branched alkyl group having 1 to 6 carbon atoms,and is for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl,s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl,1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutylgroup. With respect to Substituent group α, it is preferably a methyl ort-butyl group, and with respect to Substituent group β, it is preferablya C₁-C₄ alkyl group, and more preferably a methyl or ethyl group.

“Halogeno C₁-C₆ alkyl group” in the definition of Substituent groups αand β represents a group in which 1 to 3 of the aforementioned halogenatoms are bonded to the aforementioned C₁-C₆ alkyl group, and is forexample, a trifluoromethyl, trichloromethyl, tribromomethyl,difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl,2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl,2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexylor 2,2-dibromoethyl group, preferably a halogeno C₁-C₂ alkyl group, andmore preferably a trifluoromethyl group.

“C₁-C₆ alkoxy group” in the definition of Substituent groups α and βrepresents a group in which the aforementioned C₁-C₆ alkyl group isbonded to an oxygen atom, and is for example, a methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy,isopentoxy, 2-methylbutoxy, neopentoxy, 1-ethylpropoxy, hexyloxy,4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy,2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy,1,3-dimethylbutoxy, 2,3-dimethylbutoxy or 2-ethylbutoxy group,preferably a C₁-C₄ alkoxy group, more preferably a C₁-C₂ alkoxy group,and especially preferably a methoxy group.

“C₁-C₆ alkylthio group” in the definition of Substituent group arepresents a group in which the aforementioned C₁-C₆ alkyl group isbonded to a sulfur atom, and is for example, a methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio,t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio,neopentylthio, 1-ethylpropylthio, hexylthio, 4-methylpentylthio,3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio,3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio,1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio or2-ethylbutylthio group, preferably a C₁-C₄ alkylthio group, morepreferably a C₁-C₂ alkylthio group, and especially preferably amethylthio group.

“Amino group which may be substituted with 1 or 2 groups selected fromSubstituent group γ” in the definition of Substituent groups α and βrepresents an amino group which may be substituted with one or twogroups which may be the same or different, the group being selected fromSubstituent group γ consisting of a C₁-C₁₀ alkyl group, a C₆-C₁₀ arylgroup, a C₇-C₁₆ aralkyl group, a C₁-C₇ aliphatic acyl group, a C₇-C₁₁aromatic acyl group, a C₈-C₁₂ aromatic-aliphatic acyl group, a C₄-C₁₁cycloalkylcarbonyl group and a 5- or 6-membered aromatic heterocycliccarbonyl group containing nitrogen atom(s).

In the above definition, “C₁-C₁₀ alkyl group” in the definition ofSubstituent group γ represents a linear or branched alkyl group having 1to 10 carbon atoms, and is for example, the aforementioned C₁-C₆ alkyl,heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl,2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl,6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl,3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl,1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl,3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl or7,7-dimethyloctyl group, and is preferably a linear or branched alkylgroup having 1 to 4 carbon atoms.

In the above definition, “C₆-C₁₀ aryl group” in the definition ofSubstituent group γ represents an aromatic hydrocarbon group having 6 to10 carbon atoms, and the group may be substituted by a nitro group, theaforementioned halogen atoms, a hydroxy group, the aforementioned C₁-C₆alkyl group, a C₁-C₆ alkylcarbonyloxy group or a C₁-C₆ alkoxy group.Such group is for example, a phenyl, naphthyl, paranitrophenyl,parachlorophenyl, parafluorophenyl, parahydroxyphenyl,paraacetoxyphenyl, paramethylphenyl, paraethylphenyl, parapropylphenyl,paramethoxyphenyl, paraethoxyphenyl or parapropoxyphenyl group, and ispreferably a phenyl, paranitrophenyl or parapropoxyphenyl group.

In the above definition, “C₇-C₁₆ aralkyl group” in the definition ofSubstituent group γ represents a group in which the aforementionedC₆-C₁₀ aryl group is bonded to the aforementioned C₁-C₆ alkyl group, andis for example, a benzyl, naphthylmethyl, indenylmethyl, diphenylmethyl,1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl,1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl,2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl,3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl,3-naphthylbutyl, 4-naphthylbutyl, 5-phenylpentyl, 5-naphthylpentyl,6-phenylhexyl or 6-naphthylhexyl group, preferably an aralkyl group inwhich a phenyl group is bonded to a C₁-C₄ alkyl group, and morepreferably a benzyl group.

In the above definition, “C₁-C₇ aliphatic acyl group” in the definitionof Substituent group γ represents a group in which a hydrogen atom, or asaturated or non-saturated C₁-C₆ linear hydrocarbon group is bonded to acarbonyl group, and is for example, a formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl,methacryloyl or crotonoyl group, preferably an acetyl, propionyl orpivaloyl group, and more preferably an acetyl group.

In the above definition, “C₇-C₁₁ aromatic acyl group” in the definitionof Substituent group γ represents a group in which a C₆-C₁₀ aryl groupis bonded to a carbonyl group, and is for example, a benzoyl,1-indanecarbonyl, 2-indanecarbonyl or 1- or 2-naphthoyl group, and ispreferably a benzoyl or naphthoyl group.

In the above definition, “C₈-C₁₂ aromatic-aliphatic acyl group” in thedefinition of Substituent group γ represents a group in which a phenylgroup is bonded to a C₂-C₆ aliphatic acyl group, and is for example, aphenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, 5-phenylpentanoyl or6-phenylhexanoyl group, and is preferably a phenylacetyl group.

In the above definition, “C₄-C₁₁ cycloalkylcarbonyl group” in thedefinition of Substituent group γ represents a group in which a C₃-C₁₀cycloalkyl group (which represents a 3- to 10-membered saturated cyclichydrocarbon group which may be ring-fused, and is for example, acyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornylor adamantyl group, and preferably a C₃-C₆ cycloalkyl group) is bondedto a carbonyl group, and is for example, a cyclopropanoyl, cyclobutyryl,cyclopentanoyl, cyclohexanoyl, cycloheptylcarbonyl, norbornylcarbonyl oradamantylcarbonyl group, preferably a C₄-C₇ cycloalkylcarbonyl group,and especially preferably a cyclopentanoyl or cyclohexanoyl group.

In the above definition, “5- or 6-membered aromatic heterocycliccarbonyl group containing nitrogen atom(s)” in the definition ofSubstituent group γ represents a group in which a 5- or 6-memberedaromatic heterocyclic ring which contains at least one nitrogen atom andmay further contain a hetero atom selected from the hetero atom groupconsisting of a nitrogen atom, an oxygen atom and a sulfur atom (forexample, a pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl,oxadiazolyl or thiadiazolyl group), is bonded to a carbonyl group, andis for example, a pyrrolylcarbonyl, imidazolylcarbonyl,pyrazolylcarbonyl, triazolylcarbonyl, tetrazolylcarbonyl, nicotinoyl,isonicotinoyl, pyrazinylcarbonyl, pyrimidinylcarbonyl,pyridazinylcarbonyl, thiazolylcarbonyl, oxazolylcarbonyl,oxadiazolylcarbonyl or thiadiazolylcarbonyl group, preferably apyridylcarbonyl group, and especially preferably a nicotinoyl orisonicotinoyl group.

“Amino group which may be substituted with 1 or 2 groups selected fromSubstituent group γ” in the definition of Substituent groups α and β ispreferably an amino group or an amino group which is substituted with 1or 2 substituents (the substituents are the same or different groupseach selected from the group consisting of a C₁-C₁₀ alkyl group, aC₆-C₁₀ aryl group and a C₇-C₁₆ aralkyl group), more preferably an aminogroup or a mono- or di-C₁-C₁₀ alkylamino group, and especiallypreferably an amino, dimethylamino or isopropylamino group.

The C₃-C₁₀ cycloalkyl moiety of “C₃-C₁₀ cycloalkyl group which may besubstituted with 1 to 3 groups selected from Substituent group β” in thedefinition of Substituent group α has the same meaning as describedabove, and is preferably a C₃-C₁₀ cycloalkyl group which may besubstituted with one group selected from Substituent group β, morepreferably a C₃-C₁₀ cycloalkyl group which may be substituted with onegroup selected from the group consisting of halogen, hydroxy, C₁-C₆alkyl and halogeno C₁-C₆ alkyl, even more preferably an adamantyl groupwhich may be substituted with one of fluorine, chlorine, hydroxy,methyl, ethyl, t-butyl, trifluoromethyl, methoxy, amino, methylamino ordimethylamino, and especially preferably an adamantyl group.

With respect to the “C₆-C₁₀ aryl group which may be substituted with 1to 3 groups selected from Substituent group β” in the definition ofSubstituent group a and with respect to “C₆-C₁₀ aryl group” in thedefinition of Substituent group β, the C₆-C₁₀ aryl moiety has the samemeaning as described above, and is preferably a C₆-C₁₀ aryl group whichmay be substituted with one group selected from Substituent group β,more preferably a C₆-C₁₀ aryl group which may be substituted with one ofhalogen, hydroxy, C₁-C₆ alkyl, halogeno C₁-C₆ alkyl, C₁-C₆ alkoxy oramino which may be substituted with 1 or 2 groups selected fromSubstituent group γ, even more preferably a phenyl group which may besubstituted with one of fluorine, chlorine, hydroxy, methyl, ethyl,t-butyl, trifluoromethyl, methoxy, amino, methylamino or dimethylamino,and especially preferably a phenyl or 4-hydroxyphenyl group.

The C₇-C₁₆ aralkyl moiety of the “C₇-C₁₆ aralkyl group which may besubstituted with 1 to 3 groups selected from Substituent group β” in thedefinition of Substituent group α, has the same meaning as describedabove, and is preferably a C₇-C₁₆ aralkyl group which may be substitutedwith one group selected from Substituent group β, more preferably abenzyl group which may be substituted with one of halogen, hydroxy,C₁-C₆ alkyl, halogeno C₁-C₆ alkyl, C₁-C₆ alkoxy or amino which may besubstituted with 1 or 2 groups selected from Substituent group γ, evenmore preferably a benzyl group which may be substituted with one offluorine, chlorine, hydroxy, methyl, ethyl, t-butyl, trifluoromethyl,methoxy, amino, methylamino or dimethylamino, and especially preferablya benzyl group.

The C₆-C₁₀ aryloxy moiety of the “C₆-C₁₀ aryloxy group which may besubstituted with 1 to 3 groups selected from Substituent group β” in thedefinition of Substituent group α represents a group in which theaforementioned C₆-C₁₀ aryl is bonded to an oxygen atom, and is forexample, a phenoxy, 1-indenyloxy, 2-indenyloxy, 3-indenyloxy,1-naphthyloxy or 2-naphthyloxy group, and is preferably a phenoxy group.

The C₇-C₁₆ aralkyloxy moiety of the “C₇-C₁₆ aralkyloxy group which maybe substituted with 1 to 3 groups selected from Substituent group β” inthe definition of Substituent group a represents a group in which theaforementioned C₇-C₁₆ aralkyl group is bonded to an oxygen atom, and isfor example, benzyloxy, naphthylmethoxy, indenylmethoxy,diphenylmethoxy, 1-phenethyloxy, 2-phenethyloxy, 1-naphthylethoxy,2-naphthylethoxy, 1-phenylpropoxy, 2-phenylpropoxy, 3-phenylpropoxy,1-naphthylpropoxy, 2-naphthylpropoxy, 3-naphthylpropoxy, 1-phenylbutoxy,2-phenylbutoxy, 3-phenylbutoxy, 4-phenylbutoxy, 1-naphthylbutoxy,2-naphthylbutoxy, 3-naphthylbutoxy, 4-naphthylbutoxy, 5-phenylpentyloxy,5-naphthylpentyloxy, 6-phenylhexyloxy or 6-naphthylhexyloxy group, andis preferably a benzyloxy group.

The C₆-C₁₀ arylthio moiety of the “C₆-C₁₀ arylthio group which may besubstituted with 1 to 3 groups selected from Substituent group β” in thedefinition of Substituent group α represents a group in which theaforementioned C₆-C₁₀ aryl group is bonded to a sulfur atom, and is forexample, a phenylthio, 1-indenylthio, 2-indenylthio, 3-indenylthio,1-naphthylthio or 2-naphthylthio group, and is preferably a phenylthiogroup.

“C₁-C₇ aliphatic acyloxy group” in the definition of Substituent group αrepresents a group in which the aforementioned C₁-C₇ aliphatic acylgroup is bonded to an oxygen atom, and is for example, a formyloxy,acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy,isovaleryloxy, pivaloyloxy, hexanoyloxy, acryloyloxy, methacryloyloxy orcrotoyloxy group, and preferably an acetoxy group.

“4- to 7-membered saturated heterocyclic group containing nitrogenatom(s)” in the definition of Substituent group a represents a 4- to7-membered saturated heterocyclic group which contains at least onenitrogen atom and may further contain hetero atom(s) selected from thehetero atom group consisting of a nitrogen atom, oxygen atom and sulfuratom, and is for example, an azetidinyl, pyrrolidinyl, imidazolidinyl,thiazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl or homopiperazinyl group, preferably a pyrrolidinyl,piperidinyl or morpholinyl group, and more preferably a pyrrolidin-1-yl,piperidin-1-yl or morpholin-4-yl group.

“5- or 6-membered aromatic heterocyclic group containing nitrogenatom(s)” in the definition of Substituent group α has the same meaningas described above, and is preferably an imidazolyl, tetrazolyl orpyridinyl group, and more preferably a pyridin-2-yl or pyridin-3-ylgroup.

R is preferably a phenyl group substituted with 1 to 5 groups selectedfrom the group consisting of a halogen atom, a C₁-C₆ alkyl group, ahalogeno C₁-C₆ alkyl group, an amino group which may be substituted with1 or 2 groups selected from Substituent group γ, a 4- to 7-memberedsaturated heterocyclic group containing nitrogen atom(s) and a 5- to6-membered aromatic heterocyclic group containing nitrogen atom(s).

R is more preferably a phenyl group which is substituted with amino oramino which is substituted with 1 or 2 substituents (the substituentsare the same or different, and each is a group selected from the groupconsisting of a C₁-C₁₀ alkyl group, a C₆-C₁₀ aryl group and a C₇-C₁₆aralkyl group), and may be further substituted with 1 to 3 substituents(each substituent is a group selected from a group consisting of ahalogen atom, a C₁-C₆ alkyl group and a halogeno C₁-C₆ alkyl group).

R is even more preferably a phenyl group which is substituted with anamino or mono- or di-C₁-C₁₀ alkylamino group, and may be furthersubstituted with 1 or 2 C₁-C₆ alkyl groups.

The compound represented by the general formula (I), which is an activeingredient of a pharmaceutical composition of the present invention, ispreferably

5-(4-(6-(3-isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione

5-(4-(6-(3-(isobutyl-methyl-amino)-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione

5-(4-(6-(4-(isobutyl-methyl-amino)-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione

5-(4-(6-(3-(ethyl-isopropyl-amino)-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione

5-(4-(6-(4-isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione

5-(4-(6-(4-sec-butylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione

5-(4-(6-(4-isobutylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dioneor

5-(4-(6-(4-amino-3,5-dimethyl-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione,or a pharmacologically acceptable salt thereof, and further preferably

5-(4-(6-(4-amino-3,5-dimethyl-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride,or

5-(4-(6-(3-isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride.

The present invention provides an anti-cancer pharmaceutical compositionfor prophylaxis or treatment of carcinoma, sarcoma or hematopoieticcancer, the composition including at least one anti-cancer drug selectedfrom the group consisting of an epidermal growth factor receptor (EGFR)inhibitor, a vascular endothelial growth factor receptor (VEGFR)inhibitor and a Raf kinase inhibitor, and at least one compound selectedfrom the group consisting of a compound having peroxisome proliferatoractivated receptor (PPAR) γ activation potency or pharmacologicallyacceptable salt thereof as active ingredients, for administering theactive ingredients simultaneously or at different times.

Epidermal growth factor receptor (EGFR) is a receptor protein whichexists on the cell surface corresponding to an epidermal growth factor.The receptor is a membrane-spanning protein, and has a region within thecell where it possesses tyrosine kinase activity. It has become apparentthat the receptor is expressed on the surface of many cancer cells, andfrequent overexpression is observed expecially in lung cancer, breastcancer, colon cancer, pancreatic cancer and the like. With respect todrugs which inhibit the function of epidermal growth factor receptor(EGFR), cetuximab (trade name Erbitux) and panitumumab can be mentionedfor example as antibodies which bind with the extracellular domain. Inaddition, with respect to inhibitors against tyrosine kinase activity,gefitinib (trade name Iressa), erlotinib (trade name Tarceva) andlapatinib can be mentioned. Preferably, erlotinib (trade name Tarceva)can be mentioned.

Vascular endothelial growth factor receptor (VEGFR) is a receptorprotein which exists on the cell surface corresponding to a vascularendothelial growth factor. The receptor is a membrane-spanning protein,and has a region within the cell where it posseses tyrosine kinaseactivity. It has been known that the receptor is expressed mainly invascular endothelial cells, and promotes proliferation of vascularendothelial cells by being stimulated with vascular endothelial growthfactor secreted from cancer cells. As a result, angiogenesis in theperiphery of cancer tissue is enhanced, and proliferation of cancertissues is promoted. With respect to drugs which inhibit the function ofvascular endothelial growth factor receptor (VEGFR), bevacizumab (tradename Avastin) which is a neutralizing antibody against vascularendothelial cell growth factor itself, and sorafenib, SU11248 andvatalanib (PTK787) which are inhibitors against tyrosine kinaseactivity, can be mentioned. Preferably, sorafenib can be mentioned.

Raf kinase is one type of serine-threonine kinase which is deeplyinvolved with cell proliferation signalling, and is known to share arole in a cascade which transduces a proliferation signal from Rasprotein, which is a low molecular weight G protein, into a nucleus. Withrespect to drugs which inhibit kinase activity of Raf, sorafenib can bementioned for example.

The compound having PPAR γ activation potency, which is one of theactive ingredients of the aforementioned anti-cancer pharmaceuticalcomposition according to the present invention, includes any compoundswhich activate human PPARγ by any acceptable assay, or any compoundswhich are generally recognized as PPARγ activators or as PPARγ agonists.Such PPARγ activator may be two or more PPAR subtype activators. As forpreferable PPARγ activators, thiazolidinedione compounds which are knownto be useful for treating diabetes, and non-thiazolidinedione compoundssuch as those disclosed in U.S. Pat. No. 6,294,580 can be mentioned. Asfor preferable thiazolidinedione compounds, currently commerciallyavailable rosiglitazone and pioglitazone, and compounds disclosed inJapanese Patent No. 2976885 (U.S. Pat. No. 5,886,014), Japanese PatentNo. 3488099 (U.S. Pat. No. 6,432,993, EP Patent No. 1022272) andJapanese Patent Appication (Kokai) No. 2000-351779 (InternationalPublication No. WO 00/61581) can be mentioned in addition to thecompound represented by the general formula (I) according to the presentinvention. As for preferable non-thiazolidinedione compounds, compoundsthat are under development, such as Glaxo Smith Kline's compoundGI262570 (farglitazar) and the like can be mentioned. Among thesecompounds having a PPARγ activation potency, especially preferable arethe compound represented by the general formula (I) or apharmacologically acceptable salt thereof according to the presentinvention.

Among the compound represented by the general formula (I) according tothe present invention, the compound having a PPARγ activation potency,the epidermal growth factor receptor (EGFR) inhibitor, the vascularendothelial growth factor receptor (VEGFR) inhibitor and the Raf kinaseinhibitor, which are active ingredients of the present invention, thosewhich form salts can each be made into a salt in accordance with generalmethods, and such salts are also embraced in the present invention.

Among such salts, an inorganic acid salt such as hydrochloric acid salt,hydrobromic acid salt, sulfuric acid salt, nitric acid salt andphosphoric acid salt; carboxylic acid salt such as acetic acid salt,fumaric acid salt, maleic acid salt, oxalic acid salt, malonic acidsalt, succinic acid salt, citric acid salt and malic acid salt; asulfonic acid salt such as methanesulfonic acid salt, ethanesulfonicacid salt, benzenesulfonic acid salt and toluenesulfonic acid salt; andan amino acid salt such as glutamic acid salt and asparatic acid salt;can be mentioned, for example, as a salt with an acid.

As a salt with a base, an alkali metal salt such as lithium salt, sodiumsalt and potassium salt; an alkaline earth metal salt such as calciumsalt and magnesium salt; or an organic base salt such as ammonium salt,triethylamine salt, diisopropylamine salt and cyclohexylamine salt; canbe mentioned for example.

There are cases where each of the compound represented by the generalformula (I), the compound having a PPARγ activation potency, theepidermal growth factor receptor (EGFR) inhibitor, the vascularendothelial growth factor receptor (VEGFR) inhibitor and the Raf kinaseinhibitor, which are each an active ingredient of the pharmaceuticalcomposition according to the present invention, has an optical isomer,and each of such and a mixture thereof are all embraced in the presentinvention. Such optical isomer can be obtained by either a synthesisusing a starting material of each of the isomers, or by resolution of asynthesized compound using a general resolution method or separationmethod if desired.

There are cases where each of the compound represented by the generalformula (I), the compound having a PPARγ activation potency, theepidermal growth factor receptor (EGFR) inhibitor, the vascularendothelial growth factor receptor (VEGFR) inhibitor and the Raf kinaseinhibitor, which are each an active ingredient of the pharmaceuticalcomposition according to the present invention, exists as a hydrate oras a solvate, and each of such and a mixture thereof are all embraced inthe present invention.

The present invention provides a method for prophylaxis or treatment ofcarcinoma (especially, gastric cancer, colon cancer, lung cancer, breastcancer, pancreatic cancer, kidney cancer or prostate cancer), sarcoma(especially, medulloblastoma, rhabdomyosarcoma, Ewing's sarcoma orliposarcoma) or hematopoietic cancer (especially, multiple myeloma orleukemia), the method for prophylaxis or treatment according to thepresent invention being conducted by using the compound represented bythe aforementioned general formula (I) or a pharmacologically acceptablesalt thereof alone, or by using a combination of a compound having PPARγactivation potency (preferably the compound represented by theaforementioned general formula (I)) or a pharmacologically acceptablesalt thereof with an epidermal growth factor receptor (EGFR) inhibitor,a vascular endothelial growth factor receptor (VEGFR) inhibitor or a Rafkinase inhibitor.

In the present invention, “using a combination” means to use two or moretypes of drugs, and a form in which each of the drugs is administered atthe same time, a form in which each of them is administered aloneseparately after an interval, and a form in which they are mixed and areadministered as a physically uniform composition can be mentioned.

In the present invention, “administer at the same time” has noparticular limitation so long as it is an administration form capable ofadministering substantially at the same time; however, administration asa uniform composition is preferable.

In addition, “administer separately after an interval” has no particularlimitation so long as it is an administration form capable ofadministering separately at different times. For example, anadministration form in which the epidermal growth factor receptor (EGFR)inhibitor, the vascular endothelial growth factor receptor (VEGFR)inhibitor or the Raf kinase inhibitor is administered first, and after apredetermined time, the compound having PPARγ activation potency or apharmacologically acceptable salt thereof is administered, can bementioned.

Effects of the Invention

The anti-cancer pharmaceutical composition of the present inventionwhich contains a compound represented by the general formula (I) as anactive ingredient, is useful as an agent for prophylaxis or treatment ofgastric cancer, colon cancer, lung cancer, breast cancer, pancreaticcancer, kidney cancer, prostate cancer, medulloblastoma,rhabdomyosarcoma, Ewing's sarcoma, liposarcoma, multiple myeloma orleukemia.

The anti-cancer pharmaceutical composition according to the presentinvention, which includes at least one anti-cancer drug selected fromthe group consisting of an epidermal growth factor receptor (EGFR)inhibitor, a vascular endothelial growth factor receptor (VEGFR)inhibitor and a Raf kinase inhibitor, and at least one compound selectedfrom the group consisting of a compound having a PPARγ activationpotency and a pharmacologically acceptable salt thereof as activeingredients which are for administering simultaneously or separately atdifferent times, is useful as an anti-cancer drug (anti-cancer drug forprophylaxis or treatment of carcinoma such as gastric cancer, coloncancer, lung cancer, breast cancer, pancreatic cancer, kidney cancer andprostate cancer, sarcoma such as medulloblastoma, rhabdomyosarcoma,Ewing's sarcoma and liposarcoma, and hematopoietic cancer such asmultiple myeloma and leukemia).

BEST MODE FOR CARRYING OUT THE INVENTION

The compound represented by the general formula (I), which is an activeingredient of the pharmaceutical composition of the present invention,can be manufactured easily in accordance with the method described inJapanese Patent No. 3488099.

Rosiglitazone can be manufactured easily in accordance with the methoddisclosed in U.S. Pat. No. 5,741,803, and pioglitazone in accordancewith U.S. Pat. No. 4,687,777.

With respect to thiazolidinedione compounds having PPARγ activationpotency, which are disclosed in Japanese Patent No. 2976885 (U.S. Pat.No. 5,886,014), Japanese Patent No. 3488099 (U.S. Pat. No. 6,432,993, EPPatent No. 1022272) and Japanese Patent Appication (Kokai) No.2000-351799 (International Publication No. WO 00/61581), manufacturingmethods are also disclosed in each of the published applications, andthe compounds can be manufactured easily in accordance with the methodsdisclosed in each of the published applications.

Farglitazar can be manufactured easily in accordance with the methoddisclosed in International Publication No. WO 00/08002.

As an epidermal growth factor receptor (EGFR) inhibitor, which is anactive ingredient of the anti-cancer pharmaceutical composition of thepresent invention, the composition containing a compound having PPARγactivation potency such as a compound represented by the general formula(I) or a pharmacologically acceptable salt thereof and other anti-canceragent(s) as active ingredients, gefitinib is available from AstraZeneca.

Cetuximab can be manufactured easily in accordance with the methoddisclosed in EP Patent No. 359282, panitumumab in accordance withInternational Publication No. WO 96/33735, erlotinib in accordance withInternational Publication No. WO 96/30347, lapatinib in accordance withInternational Publication No. WO 99/35146, and among the vascularendothelial growth factor receptor (VEGFR) inhibitors, bevacizumab inaccordance with EP Patent No. 1325932, sorafenib in accordance withInternational Publication No. WO 99/35146, SU11248 in accordance withInternational Publication No. WO 2001/060814, and vatalanib inaccordance with International Publication No. WO 98/035958.

In the case where the compound represented by the general formula (I) ora pharmacologically acceptable salt thereof, which is an activeingredient of the pharmaceutical composition according to the presentinvention, is used as a therapeutic agent, a quality of life improvingagent or as a prophylactic agent, the compound or a pharmacologicallyacceptable salt thereof by itself or in a mixture with apharmacologically acceptable carrier, e.g.,an excipient, diluent and thelike that are suitably pharmacologically acceptable, can be administeredorally as a tablet, a capsule, granules, powders or syrup, orparenterally by injection or suppository.

These pharmaceutical preparations are prepared in accordance with aknown process by using additives including excipients (for example,organic excipients such as sugar derivatives, e.g. lactose, sucrose,glucose, mannitol or sorbitol; starch derivatives, e.g. corn starch,potato starch, α-starch or dextrin; cellulose derivatives, e.g.crystalline cellulose; gum arabic; dextrane; or pullulan, and inorganicexcipients such as silicate derivatives, e.g. light silicic anhydride,synthetic aluminum silicate, calcium silicate, magnesiumaluminometasilicate; phosphates, e.g. calcium monohydrogen phosphate;carbonates, e.g. calcium carbonate; and sulfuric acid salts such ascalcium sulfate, can be mentioned), lubricants (for example, stearicacid, metal salts of stearic acid such as calcium stearate or magnesiumstearate; talc; colloidal silica; waxes such as bee gum or spermaceti;boric acid; adipic acid; sulfates such as sodium sulfate; glycol;fumaric acid; sodium benzoate; DL leucine; sodium salt of fatty acid;lauryl sulfates such as sodium lauryl sulfate or magnesium laurylsulfate; silicic acids such as silicic anhydride or silicate hydrate;and the aforementioned starch derivatives can be mentioned), binders(for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,polyvinylpyrrolidone, macrogol and compounds similar to theaforementioned excipient can be mentioned), disintegrants (for example,cellulose derivatives such as low-substituted hydroxypropyl cellulose,carboxymethyl cellulose, calcium carboxymethyl cellulose or internallycrosslinked sodium carboxymethyl cellulose; or chemically modifiedstarches or celluloses such as carboxymethyl starch, sodiumcarboxymethyl starch or crosslinked polyvinylpyrrolidone can bementioned), stabilizers (for example, esters of para-hydroxybenzoic acidsuch as methyl paraben or propyl paraben; alcohols such aschlorobutanol, benzyl alcohol or phenyl ethyl alcohol, benzalkoniumchloride; phenols such as phenol or cresol; thimerosal; dehydroaceticacid; and sorbic acid can be mentioned) and corrigents for flavor andsmell (for example, commonly used sweeteners, acidifiers or fragrancescan be mentioned) or diluents.

The dosage amount varies to a large extent depending on conditions suchas the activity of the drug, the symptoms, age, weight and the like ofthe patient (warm-blooded animal, especially human). For humans, it isdesirable to administer (orally or by intravenous injection) a dosage of0.0005 mg/kg to 50 mg/kg. Preferably the range is from 0.0005 mg/kg to 1mg/kg, and more preferably from 0.001 mg/kg to 0.1 mg/kg, per dose. Forwarm-blooded animals other than human, for example, mouse, the dosagerange is from 0.0005 mg/kg to 50 mg/kg, and preferably from 0.01 mg/kgto 10 mg/kg. The drug (dose) may be administered 1 to 6 times per dayand preferably 1 to 2 times per day, depending on the symptoms.

In addition, the compound having PPARγ activation potency (preferably acompound represented by the general formula (I)) or a pharmacologicallyacceptable salt thereof, and the epidermal growth factor receptor (EGFR)inhibitor, the vascular endothelial growth factor receptor (VEGFR)inhibitor or the Raf kinase inhibitor can each be formulated alone in aseparate administration form, or can be formulated into a physicallyuniform administration form by mixing them.

When each of such separate administration form or uniform administrationform is used, each of the compound having PPARγ activation potency or apharmacologically acceptable salt thereof, the epidermal growth factorreceptor (EGFR) inhibitor, the vascular endothelial growth factorreceptor (VEGFR) inhibitor and the Raf kinase inhibitor or a mixturewith a pharmaceutically acceptable carrier, e.g., an excipient ordiluent can be administered orally by a tablet, a capsule, granules,powders or syrup, or parenterally by injection or suppository.

These pharmaceutical preparations are prepared in accordance with aknown process by using additives including excipients (for example,organic excipients such as sugar derivatives, e.g. lactose, sucrose,glucose, mannitol or sorbitol; starch derivatives, e.g. corn starch,potato starch, α-starch or dextrin; cellulose derivatives, e.g.crystalline cellulose; gum arabic; dextrane; or pullulan, and inorganicexcipients such as silicate derivatives, e.g. light silicic anhydride,synthetic aluminum silicate, calcium silicate, magnesiumaluminometasilicate; phosphates, e.g. calcium monohydrogenphosphate;carbonates, e.g. calcium carbonate; and sulfuric acid salts such ascalcium sulfate, can be mentioned), lubricants (for example, stearicacid, metal salts of stearic acid such as calcium stearate or magnesiumstearate; talc; colloidal silica; waxes such as beeswax or spermaceti;boric acid; adipic acid; sulfates such as sodium sulfate; glycol;fumaric acid; sodium benzoate; DL leucine; lauryl sulfates such assodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such assilicic anhydride or silicate hydrate; and the aforementioned starchderivatives can be mentioned), binders (for example, hydroxypropylcellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone,macrogol and compounds similar to the aforementioned excipient can bementioned), disintegrants (for example, cellulose derivatives such aslow-substituted hydroxypropyl cellulose, carboxymethyl cellulose,calcium carboxymethyl cellulose or internally crosslinked sodiumcarboxymethyl cellulose; or chemically modified starches or cellulosessuch as carboxymethyl starch, sodium carboxymethyl starch or crosslinkedpolyvinylpyrrolidone can be mentioned), emulsifiers (for examplecolloidal clays such as bentonite and bee gum; metal hydroxides such asmagnesium hydroxide and aluminum hydroxide; anionic surfactants such assodium lauryl sulfate and calcium stearate; cationic surfactants such asbenzalkonium chloride; and, nonionic surfactants such as polyoxyethylenealkyl ether, polyoxyethylene sorbitan fatty acid ester, and sucrosefatty acid ester), stabilizers (for example, esters ofpara-hydroxybenzoic acid such as methyl paraben or propyl paraben;alcohols such as chlorobutanol, benzyl alcohol or phenyl ethyl alcohol;benzalkonium chloride; phenols such as phenol or cresol; thimerosal;dehydroacetic acid; and sorbic acid can be mentnioned) and corrigentsfor flavor and smell (for example, commonly used sweeteners, acidifiersor fragrances can be mentioned) or diluents.

The administration ratio of the compound having PPARγ activation potencyor a pharmacologically acceptable salt thereof, and the epidermal growthfactor receptor (EGFR) inhibitor, the vascular endothelial growth factorreceptor (VEGFR) inhibitor or the Raf kinase inhibitor may varydepending on various conditions such as the activity of the individualdrugs, and symptoms, age, weight of the patient.

Although its dosage amount varies depending on the activity ofindividual drugs, and symptom, age, weight and the like of a patient(warm-blooded animal, especially human), in the case of oraladministration for example, it is desirable to administer from 0.1 mg/kgto 100 mg/kg (preferably 0.1 mg/kg to 20 mg/kg) per dose, and in thecase of intravenous injection, it is desirable to administer from 0.01mg/kg to 100 mg/kg (preferably 0.1 mg/kg to 10 mg/kg) per dose, 1 to 6times a day (preferably 1 to 2 times per day), depending on the symptom,at the same time or separately after some time.

Further, the ratio of (i) the compound having PPAR γ activation potency,and (ii) the epidermal growth factor receptor (EGFR) inhibitor, thevascular endothelial growth factor receptor (VEGFR) inhibitor or the Rafkinase inhibitor in a dose may vary to a large extent. However, theratio of dosage amount of the (a) compound having PPARγ activationpotency or a pharmacologically acceptable salt thereof, and (b) theepidermal growth factor receptor (EGFR) inhibitor, the vascularendothelial growth factor receptor (VEGFR) inhibitor or the Raf kinaseinhibitor may be in the range of 1:1000 to 1000:1 (i.e., 1 to 0.001) inweight ratio, preferably the ratio is 1:1000 to 1:10 and more preferably1:1000 to 1:100.

EXAMPLES

Hereinafter, the present invention will be described in more detail withreference to production examples, test examples and preparationexamples; however, the scope of the present invention is not intended tobe limited to these.

Production Example 15-(4-(6-(3-Isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride

A mixture of 0.74 g ofN-(2-amino-5-(3-isopropylamino-phenoxy)-phenyl)-N-methylcarbamic acidt-butyl ester obtained in Reference Example 2, 0.70 g of4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxyacetic acid (Japanese PatentApplication (Kokai) No. Hei 11-193276), 0.41 g of diethylcyanophosphonate, 0.25 g of triethylamine, and 30 ml of anhydroustetrahydrofuran was stirred at room temperature for 4.5 hours. Thereaction mixture was concentrated, followed by addition of water andextraction with ethyl acetate. After the extraction solution was driedover anhydrous sodium sulfate, the solvent was distilled off, and theresulting residue was purified by silica gel column chromatography(eluting solvent: ethyl acetate/n-hexane=2/3) to giveN-(5-(3-isopropylamino-phenoxy)-2-(4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxyacetylamino)-phenyl)-N-methylcarbamicacid t-butyl ester as an intermediate. After this intermediate wasdissolved in 50 ml of 4N hydrochloric acid/1,4-dioxane, the mixture wasleft to stand at room temperature for 16 hours, and the product whichdeposited was filtered and washed with ethyl acetate to give the titlecompound (0.76 g, 64% yield).

¹H-NMR (DMSO-d₆)δ: 1.21 (6H, d, J=6.4 Hz), 3.11 (1H, dd, J=14 and 9.0Hz), 3.34 (1H, dd, J=14 and 4.4 Hz), 3.57-3.65 (1H, m), 3.95 (3H, s),4.91 (1H, dd, J=9.0 and 4.4Hz), 5.63 (2H, s), 6.70-7.20 (3H, m), 7.14(2H, d, J=8.7 Hz), 7.25 (2H, d, J=8.7 Hz), 7.25 (1H, d, J=3.3 Hz),7.35-7.45 (1H, m), 7.68 (1H, d, J=1.9 Hz), 7.83 (1H, d, J=8.9 Hz), 12.05(1H, s; disappeared due to addition of deuterium oxide).

Production Example 25-(4-(6-(3-(Isobutyl-methyl-amino)-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride

N-(2-amino-5-(3-(isobutyl-methyl-amino)phenoxy)-phenyl)-N-methylcarbamicacid t-butyl ester obtained in Reference Example 5 was used in place ofN-(2-amino-5-(3-isopropylamino-phenoxy)-phenyl)-N-methylcarbamic acidt-butyl ester of Production Example 1 to give the title compound insimilar manner to Production Example 1.

¹H-NMR (DMSO-d₆)δ: 0.86 (6H, d, J=6.7 Hz), 1.90-1.99 (1H, m), 2.91 (3H,s), 3.08-3.14 (3H, m), 3.34 (1H, dd, J=14 and 4.4 Hz), 3.94 (3H, s),4.91 (1H, dd, J=9.0 and 4.4 Hz), 5.65 (2H, s), 6.21 (1H, br), 6.39 (1H,br), 6.53 (1H, br), 7.15-7.27 (6H, m), 7.62 (1H, d, J=2.1 Hz), 7.80 (1H,d, J=8.9 Hz), 12.04 (1H, br; disappeared due to addition of deuteriumoxide).

Production Example 35-(4-(6-(4-(Isobutyl-methyl-amino)-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride

N-(2-methyl-5-(4-(isobutyl-methyl-amino)phenoxy)-phenyl)methylamineobtained in Reference Example 8 was used in place ofN-(2-amino-5-(3-isopropylamino-phenoxy)-phenyl)-N-methylcarbamic acidt-butyl ester of Production Example 1 to give the title compound insimilar manner to Production Example 1.

¹H-NMR (DMSO-d₆)δ: 0.90 (6H, d, J=4.4 Hz), 1.75-2.05 (1H, m), 1.99 (3H,s), 2.90-3.10 (2H, m), 3.11 (1H, dd, J=14 and 8.9 Hz), 3.34 (1H, dd,J=14 and 4.4 Hz), 3.92 (3H, s), 4.91 (1H, dd, J=8.9 and 4.4 Hz), 5.62(2H, s), 6.65-7.20 (5H, m), 7.13 (2H, d, J=8.7 Hz), 7.25 (2H, d, J=8.7Hz), 7.45-7.60 (1H, m), 7.78 (1H, d, J=8.9 Hz), 12.05 (1H, s;disappeared by addition of deuterium oxide).

Production Example 45-(4-(6-(3-(Ethyl-isopropyl-amino)-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione

A mixture of 620 mg of5-(4-(6-(3-isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochlorideobtained in Production Example 1, 66 mg of acetaldehyde, 90 mg of aceticacid, 318 mg of sodium triacetoxyborohydride and 15 ml of anhydroustetrahydrofuran was stirred at room temperature for 1 hour. The reactionmixture was concentrated, followed by addition of water and extractionwith ethyl acetate. After the extraction solution was dried overanhydrous sodium sulfate, the solvent was distilled off, and theresulting residue was purified by silica gel column chromatography(eluting solvent: ethyl acetate/n-hexane=1/1) to give the title compound(260 mg, 48% yield).

¹H-NMR (DMSO-d₆)δ: 1.06 (3H, t, J=7.0 Hz), 1.11 (6H, d, J=6.6 Hz), 3.05(1H, dd, J=14 and 9.2 Hz), 3.18 (2H, q, J=7.0 Hz), 3.31 (1H, dd, J=14and 4.3 Hz), 3.79 (3H, s), 3.94-4.04 (1H, m), 4.87 (1H, dd, J=9.2 and4.3 Hz), 5.63 (2H, s), 6.11 (1H, dd, J=7.9 and 2.0 Hz), 6.34 (1H, t,J=2.2 Hz), 6.46 (1H, dd, J=8.5 and 2.3 Hz), 6.92 (1H, dd, J=8.8 and 2.2Hz), 7.06-7.11 (3H, m), 7.19 (1H, d, J=8.7 Hz), 7.28 (1H, d, J=2.3 Hz),7.63 (1H, d, J=8.7 Hz), 12.02 (1H, s; disappeared due to addition ofdeuterium oxide).

Production Example 55-(4-(6-(4-Isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione

5-(4-(6-(4-Amino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride(Japanese Patent Application (Kokai) No. Bei 11-193276) was used inplace of5-(4-(6-(3-isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochlorideof Production Example 4, and acetone was used in place of acetaldehydeto give the title compound in similar manner to Production Example 4.

¹H-NMR (DMSO-d₆)δ: 1.13 (6H, d, J=6.3 Hz), 3.05 (1H, dd, J=14 and 9.1Hz), 3.31 (1H, dd, J=14 and 4.3 Hz), 3.45-3.52 (1H, m), 3.75 (3H, s),4.87 (1H, dd, J=9.1 and 4.3 Hz), 5.24 (1H, br; disappeared due toaddition of deuterium oxide), 5.34 (2H, s), 6.56 (2H, dd, J=12 and 3.3Hz), 6.81 (2H, d, J=8.6 Hz), 6.83 (1H, dd, J=8.2 and 2.3 Hz), 7.04-7.07(3H, m), 7.19 (2H, d, J=8.6 Hz), 7.57 (1H, d, J=8.8 Hz), 12.02 (1H, br;disappeared due to addition of deuterium oxide).

Production Example 65-(4-(6-(4-sec-Butylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione

5-(4-(6-(4-Amino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloridewas used in place of5-(4-(6-(3-isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochlorideof Production Example 4, and methyl ethyl ketone was used in place ofacetaldehyde to give the title compound in similar manner to ProductionExample 4.

¹H-NMR (DMSO-d₆)δ: 0.90 (3H, t, J=7.4 Hz), 2.17 (3H, d, J=6.4 Hz),1.34-1.46 (1H, m), 1.48-1.59 (1H, m), 3.06 (1H, dd, J=14 and 9.2 Hz),3.24-3.34 (2H, m), 3.75 (3H, s), 4.87 (1H, dd, J=9.2 and 4.3 Hz), 5.23(1H, br; disappeared due to addition of deuterium oxide), 5.34 (2H, s),6.57 (2H, d, J=8.7 Hz), 6.81 (2H, d, J=8.9 Hz), 6.84 (1H, dd, J=8.8 and2.2 Hz), 7.01-7.09 (3H, m), 7.19 (2H, d, J=8.7 Hz), 7.57 (1H, d, J=8.8Hz), 12.01 (1H, br; disappeared due to addition of deuterium oxide).

Production Example 75-(4-(6-(4-Isobutylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione

5-(4-(6-(4-Amino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloridewas used in place of5-(4-(6-(3-isopropylamino-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochlorideof Production Example 4, and isobutyl aldehyde was used in place ofacetaldehyde to give the title compound in similar manner to ProductionExample 4.

¹H-NMR (DMSO-d₆)δ: 0.94 (6H, d, J=6.7 Hz), 1.77-1.88 (1H, m), 2.78-2.81(2H, m), 3.05 (1H, dd, J=14 and 9.3 Hz), 3.31 (1H, dd, J=14 and 4.3 Hz),3.74 (3H, s), 4.86 (1H, dd, J=9.3 and 4.3 Hz), 5.34 (2H, s), 5.50 (1H,s; disappeared due to addition of deuterium oxide), 6.57 (2H, dd, J=6.8and 2.0 Hz), 6.81 (2H, d, J=8.8 Hz), 6.83 (1H, dd, J=8.6 and 2.4 Hz),7.04-7.07 (3H, m), 7.19 (2H, d, J=8.6 Hz), 7.56 (1H, d, J=8.8 Hz), 12.01(1H, s; disappeared due to addition of deuterium oxide).

Production Example 8

5-(4-(6-(4-Amino-3,5-dimethyl-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochloride

N-(2-Amino-5-(4-t-butoxycarbonylamino-3,5-dimethyl-phenoxy)-phenyl)-N-methylcarbamicacid t-butyl ester obtained in Reference Example 11 was used in place ofN-(2-amino-5-(3-isopropylamino-phenoxy)-phenyl)-N-methylcarbamic acidt-butyl ester of Production Example 1 to give the title compound insimilar manner to Production Example 1.

¹H-NMR (DMSO-d₆)δ: 2.34 (6H, s), 3.10 (1H, dd, J=14 and 9.0 Hz), 3.34(1H, dd, J=14 and 4.4 Hz), 3.93 (3H, s), 4.91 (1H, dd, J=4.4 and 9.0Hz), 5.62 (2H, s), 6.80 (2H, s), 7.14 (2H, d, J=8.7 Hz), 7.18 (1H, dd,J=8.9 and 2.2 Hz), 7.25 (2H, d, J=8.7 Hz), 7.61 (1H, d, J=2.2 Hz), 7.81(1H, d, J=8.9 Hz), 12.1 (1H, br; disappeared due to addition ofdeuterium oxide).

Reference Example 1N-(5-(3-Aminophenoxy)-2-nitrophenyl)-N-methylcarbamic acid t-butyl ester

To a 80 ml of anhydrous N,N-dimethylformamide suspension containing 2.18g of sodium hydride (55 wt %) was added 5.45 g of 3-aminophenol, and themixture was stirred at room temperature for 20 minutes. Subsequently,14.3 g of N-(5-chloro-2-nitrophenyl)-N-methylcarbamic acid t-butyl ester(Japanese Patent Application (Kokai) No. Hei 11-193276) was added insmall amounts, and the mixture was stirred at 100° C. for 6 hours. Thereaction mixture was concentrated, followed by addition of water andneutralization using 3N hydrochloric acid and sodium bicarbonate powder.The insoluble product which deposited was filtered, washed with water,and then dried under reduced pressure to give the title compound (16.6g, 92% yield).

¹H-NMR (DMSO-d₆)δ: 1.23 and 1.42 (9H in total, s each), 3.18 (3H, s),5.38 (2H, s; disappeared due to addition of deuterium oxide), 6.25 (1H,dd, J=7.6 and 2.4 Hz), 6.31 (1H, s), 6.46 (1H, dd, J=8.1 and 1.0 Hz),6.88 (1H, dd, J=9.0 and 2.1 Hz), 7.09 (1H, t, J=8.0 Hz), 7.16 (1H, s),8.00 (1H, d, J=9.0 Hz).

Reference Example 2N-(2-Amino-5-(3-isopropylamino-phenoxy)-phenyl)-N-methylcarbamic acidt-butyl ester

A mixture of 14.4 g ofN-(5-(3-aminophenoxy)-2-nitrophenyl)-N-methylcarbamic acid t-butylester, 2.90 g of acetone, 3.00 g of acetic acid, 10.6 g of sodiumtriacetoxyborohydride and 200 ml of anhydrous tetrahydrofuran wasstirred at room temperature for 4 days. The reaction mixture wasconcentrated, followed by addition of water and extraction with ethylacetate. After the extraction solution was dried over anhydrous sodiumsulfate, the solvent was distilled off, and the resulting residue waspurified by silica gel column chromatography (eluting solvent: ethylacetate/n-hexane=2/3) to giveN-(5-(3-isopropylamino-phenoxy)-2-nitrophenyl)-N-methylcarbamic acidt-butyl ester, as an intermediate. This intermediate was dissolved in200 ml of methanol, followed by addition of 2.02 g of 10%palladium-carbon, and the mixture was vigorously stirred under ahydrogen atmosphere at room temperature for 2.5 hours. After completionof the reaction, the catalyst was filtered, and the solvent wasdistilled off to give the title compound (12.0 g, 81% yield).

¹H-NMR (DMSO-d₆)δ: 1.08 (6H, d, J=6.4 Hz), 1.29 (9H, s), 2.98 (3H, s),3.40-3.47 (1H, m), 4.78 (2H, s; disappeared due to addition of deuteriumoxide), 5.45 (1H, d, J=7.8 Hz; disappeared due to addition of deuteriumoxide), 5.96 (1H, d, J=7.2 Hz), 6.07 (1H, t, J=2.2 Hz), 6.20 (1H, dd,J=8.1 and 1.9 Hz), 6.60 (1H, s), 6.71 (2H, s), 6.93 (1H, t, J=8.1 Hz).

Reference Example 3N-(5-(3-Bromophenoxy)-2-nitrophenyl)-N-methylcarbamic acid t-butyl ester

To a 50 ml of anhydrous N,N-dimethylformamide suspension containing 2.5g of sodium hydride (55% weight) was added 10.0 g of 3-bromophenol, andthe mixture was stirred under ice-cooling for 15 minutes. Subsequently,a solution of 16.6 g of N-(5-chloro-2-nitrophenyl)-N-methylcarbamic acidt-butyl ester dissolved in 70 ml of anhydrous N,N-dimethylformamide wasadded to the mixture in drops, and the mixture was stirred at 100° C.for 3 hours. The reaction mixture was concentrated, followed by additionof water, neutralization using 3N hydrochloric acid and extraction withethyl acetate. The extraction solution was washed with saturated saline,and then dried over anhydrous sodium sulfate. Ethyl acetate wasdistilled off from the extraction solution, and the insoluble productwhich deposited was washed with hexane and filtered, followed by dryingunder reduced pressure, to give the title compound (20.2 g, 83% yield).

¹H-NMR (CDCl₃)δ: 1.24 (9H, s), 3.19 (3H, s), 6.97 (1H, dd, J=9.0 and 2.4Hz), 7.22 (1H, d, J=7.9 Hz), 7.29 (1H, d, J=1.7 Hz), 7.42-7.51 (3H, m),8.03 (1H, d, J=9.0 Hz).

Reference Example 4N-(5-(3-(Isobutyl-methyl-amino)phenoxy)-2-nitrophenyl)-N-methylcarbamicacid t-butyl ester

700.0 mg of N-(5-(3-bromophenoxy)-2-nitrophenyl)-N-methylcarbamic acidt-butyl ester obtained in Reference Example 3, 0.24 ml ofisobutylmethylamine, 151.0 mg of tris(dibenzylideneacetone)dipalladium,115.7 mg of 2-(dicyclohexylphosphino)biphenyl and 277.7 mg of potassiumt-butoxide were suspended in 4 ml of anhydrous toluene, and the mixturewas stirred at 100° C. for 1.5 hours. Water was added to the reactionmixture, followed by extraction with ethyl acetate. After the extractedsolution was washed with saturated saline and dried over anhydroussodium sulfate, the solvent was distilled off, and the resulting residuewas purified by silica gel column chromatography (eluting solvent: ethylacetate/n-hexane=1/7) to give the title compound (204.2 mg, 29% yield).

¹H-NMR (CDCl₃)δ: 0.80 (6H, d, J=6.6 Hz), 1.25 (9H, s), 1.88-2.01 (1H,m), 2.85 (3H, s), 2.95 (2H, d, J=7.3 Hz), 3.14 (3H, s), 6.20-6.27 (2H,m), 6.43 (1H, dd, J=8.8 and 2.2 Hz), 6.72-6.83 (2H, m), 7.11 (1H, t,J=8.1 Hz), 7.81 (1H, d, J=9.5 Hz).

Reference Example 5N-(2-Amino-5-(3-(isobutyl-methyl-amino)phenoxy)-phenyl)-N-methylcarbamicacid t-butyl ester

204.2 mg ofN-(5-(3-(isobutyl-methyl-amino)phenoxy)-2-nitrophenyl)-N-methylcarbamicacid t-butyl ester obtained in Reference Example 4 was dissolved in 10ml of ethanol, followed by addition of 100.0 mg of 10% palladium-carbon,and the mixture was stirred vigorously under a hydrogen atmosphere atroom temperature for 2.5 hours. After completion of the reaction, thecatalyst was filtered, and the solvent was distilled off. The resultingresidue was purified by silica gel column chromatography (elutingsolvent: ethyl acetate/n-hexane=1/4→1/3) to give the title compound(145.4 mg, 77% yield).

¹H-NMR (CDCl₃)δ: 0.90 (6H, d, J=6.6 Hz), 1.57 (9H, s), 1.98-2.09 (1H,m), 2.92 (3H, s), 3.06 (2H, d, J=7.3 Hz), 3.13 (3H, s), 3.64 (2H, s;lost due to addition of deuterium oxide), 6.30 (1H, t, J=2.2 Hz), 6.35(1H, dd, J=8.1 and 2.2 Hz), 6.70-6.88 (3H, m), 7.08 (1H, t, J=8.2 Hz),7.25-7.31 (1H, m).

Reference Example 6(4-(Isobutyl-methyl-amino)phenoxy)-t-butyldimethylsilane

5 ml of (4-bromophenoxy)-t-butyldimethylsilane, 2.9 ml ofisobutylmethylamine, 458.0 mg of palladium acetate, 1.2 g of 2-(dit-butylphosphino)biphenyl and 2.9 g of sodium t-butoxide were suspendedin 40 ml of anhydrous toluene, and the mixture was stirred at 100° C.for 1.5 hours. The catalyst was filtered, followed by addition of waterand extraction with ethyl acetate. After the extraction solution waswashed with saturated saline and dried over anhydrous sodium sulfate,the solvent was distilled off, and the resulting residue was purified bysilica gel column chromatography (eluting solvent: ethylacetate/n-hexane=1/40→1/20) to give the title compound (3.83 g, 64%yield).

¹H-NMR (CDCl₃)δ: 0.16 (6H, s), 0.91 (6H, d, J=6.6 Hz), 0.97 (9H, s),1.94-2.05 (1H, m), 2.87 (3H, s), 2.98 (2H, d, J=7.3 Hz), 6.57 (2H, d,J=8.8 Hz), 6.72 (2H, d, J=8.8 Hz).

Reference Example 7N-(5-(4-(Isobutyl-methyl-amino)phenoxy)-2-nitrophenyl)methylamine

3.83 g of (4-(isobutyl-methyl-amino)phenoxy)-t-butyldimethylsilaneobtained in Reference Example 6 was dissolved in 20 ml of anhydroustetrahydrofuran, followed by addition of 20 ml of 1Mtetra-n-butylammonium fluoride tetrahydrofuran solution, and the mixturewas stirred at room temperature for 30 minutes. The reaction mixture wasconcentrated, followed by addition of water and extraction with ethylacetate. After the extraction solution was washed with saturated salineand dried over anhydrous sodium sulfate, the solvent was distilled off,and the resulting residue was purified by silica gel columnchromatography (eluting solvent: ethyl acetate/n-hexane=1/5). Theresulting product was dissolved in 4N hydrochloric acid-1,4-dioxane, andthe mixture was stirred at room temperature for 30 minutes. The reactionliquid was concentrated and washed with diethyl ether to give4-isobutylmethylaminophenol.monohydrochloride, which is an intermediate.20 ml of anhydrous N,N-dimethylformamide suspension containing 500.0 mgof this intermediate and 2.6 g of potassium carbonate was stirred atroom temperature for 15 minutes. Subsequently, 664.7 mg ofN-(5-chloro-2-nitrophenyl)-N-methylcarbamic acid t-butyl ester was addedto the mixture, and the mixture was stirred at 150° C. for 3 hours. Thereaction mixture was concentrated, followed by addition of water andextraction with ethyl acetate. After the extraction solution was washedwith saturated saline and dried over anhydrous sodium sulfate, thesolvent was distilled off, and the resulting residue was purified bysilica gel column chromatography (eluting solvent: ethylacetate/toluene=1/30) to give the title compound (256.1 mg, 34% yield).

¹H-NMR (CDCl₃)δ: 0.96 (6H, d, J=6.8 Hz), 2.00-2.13 (1H, m), 2.92 (3H, d,J=5.9 Hz), 2.98 (3H, s), 3.12 (2H, d, J=7.8 Hz), 6.19-6.23 (2H, m), 6.68(2H, d, J=8.8 Hz), 6.96 (2H, d, J=8.8 Hz), 8.13 (1H, d, J=9.8 Hz).

Reference Example 8N-(2-Methyl-5-(4-(isobutyl-methyl-amino)phenoxy)-phenyl)methylamine

N-(5-(4-(isobutyl-methyl-amino)phenoxy)-2-nitrophenyl)methylamineobtained in Reference Example 7 was used in place ofN-(5-(3-(isobutyl-methyl-amino)phenoxy)-2-nitrophenyl)-N-methylcarbamicacid t-butyl ester of Reference Example 5 to give the title compound insimilar manner to Reference Example 5.

¹H-NMR (CDCl₃)δ: 0.88 (6H, d, J=6.6 Hz), 1.94-2.04 (1H, m), 2.77 (3H,s), 2.87 (3H, s), 2.99 (2H, d, J=7.3 Hz), 3.22 (2H, s), 6.16 (1H, dd,J=8.1 and 2.5 Hz), 6.33 (1H, d, J=2.5 Hz), 6.57 (1H, d, J=8.1 Hz), 6.59(2H, d, J=8.8 Hz), 6.87 (2H, d, J=8.8 Hz).

Reference Example 9N-(5-(4-Amino-3,5-dimethylphenoxy)-2-nitrophenyl)-N-methylcarbamic acidt-butyl ester

4-Amino-3,5-dimethylphenol was used in place of 3-aminophenol ofReference Example 1 and the same treatment was carried out in similarmanner to Reference Example 1, followed by purification by silica gelcolumn chromatography (eluting solvent: ethyl acetate/n-hexane=1/2) togive the title compound.

¹H-NMR (DMSO-d₆)δ: 1.23 and 1.41 (total 9H, s each), 2.10 (6H, s), 3.17(3H, s), 4.66 (2H, br; disappeared due to addition of deuterium oxide),6.69 (2H, s), 6.75 (1H, dd, J=9.1 and 2.5 Hz), 7.07 (1H, s), 7.96 (1H,d, J=9.1).

Reference Example 10N-(5-(4-t-Butoxycarbonylamino-3,5-dimethylphenoxy)-2-nitrophenyl)-N-methylcarbamicacid t-butyl ester

A mixture of 2.27 g ofN-(5-(4-amino-3,5-dimethylphenoxy)-2-nitrophenyl)-N-methylcarbamic acidt-butyl ester, 1.28 g of di-t-butyl bicarbonate, 0.59 g of triethylamineand 20 ml of anhydrous tetrahydrofuran was heated under reflux for 6hours. The reaction mixture was concentrated, followed by addition ofwater and extraction with ethyl acetate. After the extraction solutionwas dried over anhydrous sodium sulfate, the solvent was distilled off,and the resulting residue was purified by silica gel columnchromatography (eluting solvent: ethyl acetate/n-hexane=1/10) to givethe title compound (1.74 g, 61% yield).

¹H-NMR (DMSO-d₆)δ: 1.24 and 1.42 (total 9H, s each), 1.46 (9H, s), 2.17(6H, s), 3.19 (3H, s), 6.84 (1H, dd, J=9.0 and 2.7), 6.90 (2H, s), 7.21(1H, s), 8.00 (1H, d, J=9.0), 8.42 (1H, s; disappeared due to additionof deuterium oxide).

Reference Example 11N-(2-Amino-5-(4-t-butoxycarbonylamino-3,5-dimethyl-phenoxy)-phenyl)-N-methylcarbamicacid t-butyl ester

N-(5-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)-2-nitrophenyl)-N-methylcarbamicacid t-butyl ester obtained in Reference Example 10 was used in place ofN-(5-(3-(isobutylmethyl-amino)phenoxy)-2-nitrophenyl)-N-methylcarbamicacid t-butyl ester ester of Reference Example 5, and the process wascarried out analogously to Reference Example 5, followed by purificationby silica gel column chromatography (elution solvent: ethylacetate/n-hexane=1/2) to give the title compound.

¹H-NMR(DMSO-d₆)δ: 1.30 and 1.37 (total 9H, s each), 1.44 (9H, s), 2.07(6H, s), 2.98 (3H, s), 4.83 (2H, br; disappeared due to addition ofdeuterium oxide), 6.54 (2H, s), 6.58-6.74 (3H, m), 8.22 (1H, s;disappeared due to addition of deuterium oxide).

Test Example 1 Evaluation of Cancer Cell Proliferation InhibitoryActivity

Human gastric cancer cell line (MKN74, MKN28) purchased fromImmuno-Biological Laboratories Co., Ltd., human breast cancer cell line(ZR-75-1), small-cell lung cancer line (SBC-1), pancreatic cancer cellline (AsPC-1), prostate cancer cell line (DU-145), kidney cancer cellline (ACHN), medulloblastoma line (D341 Med), human sarcoma cell line(rhabdomyosarcoma line A-204, Ewing's sarcoma line RD-ES, liposarcomaline SW872) and multiple myeloma line (U266) that were purchased fromAmerican Tissue Culture Collection were used in the test. MKN74, MKN28,ZR-75-1, SBC-1 and AsPC-1 were cultivated using 10% fetal bovine serum(Hyclone Laboratories, Inc.,)-RPMI (Invitrogen Corporation), RD-ES using15% fetal bovine serum (Hyclone Laboratories, Inc.)-RPMI (InvitrogenCorporation), D341 Med using 10% fetal bovine serum (HycloneLaboratories, Inc.)-MEMα (Invitrogen Corporation), ACHN using 10% fetalbovine serum (Hyclone Laboratories, Inc.)-E-MEM (InvitrogenCorporation), SW872 using 10% fetal bovine serum (Hyclone Laboratories,Inc.)-L15 (Invitrogen Corporation), A-204 using 10% fetal bovine serum(Hyclone Laboratories, Inc.)-McCoy's 5A (Invitrogen Corporation), andU266 using 0.5% fetal bovine serum (Hyclone Laboratories, Inc.)-2 ng/mLIL-6 (Genzyme Corporation)-RPMI (Invitrogen Corporation).

The cells were each inoculated on a 96-well plate for cell cultivation(Nalge Nunc International K.K.) at 1000 to 10000 cells/well, and at thesame time, the compound of Production Example 8 having PPARγ activatingaction (hereinafter referred to as Compound X, and in FIGS. 1, 2 and 3expressed as Compound X) dissolved in dimethyl sulfoxide (DMSO: DojindoLaboratories) was added to each well so that the concentration of DMSOwas 0.1% and the concentration of Compound X was 0.1, 1, or 10 μM (inthe case of AsPC-1, 0.05, 0.5 or 5 μM). To the control group was addedonly DMSO so that its concentration became 0.1%. Then, the plate forcell cultivation was cultivated in the presence of 5% carbon dioxide at37° C. for 7 days. Here, in the case of the U266 cells, cultivation wascarried out for 4 days. After completion of the cultivation, 50%trichloroacetic acid (Wako Pure Chemical Industries, Ltd.) solution wasadded to the cell cultivation solution so that its final concentrationbecame 10%, and the plate was left to stand at 4° C. for 1 hour to allowimmobilization of the cells. Subsequently, each well was washed withdistilled water 5 times, followed by adding 100 μL of 0.4%sulforhodamine B (Molecular Probes)-1% acetic acid solution to each ofthe wells and leaving them to stand for 30 minutes, thus staining thecells. Then, each well was washed with a 1% acetic acid solution 5 timesand was air-dried. 10 mM Tris was added at 150 mL/well to each well inwhich cancer cells were immobilized and stained, and absorbance A490 ofeach well was measured using MICROPLATE READER Model 3550 (Bio-RadLaboratories, Inc.). The average absorbance of each of the groups, whichhad been treated with respective concentration of the Compound X, waspresented as a percentage expression, by taking the average absorbanceof the control group, which had been treated with DMSO, as 100%.Accordingly, the cancer cell proliferation inhibitory activity ofCompound X was considered.

The results are shown in FIGS. 1, 2 and 3. In each of the graphs, thelongitudinal axis represents the absorbance [%], and the horizontal axisrepresents the concentration of Compound X [μM].

As seen in FIGS. 1, 2 and 3, Compound X showed significant proliferationinhibitory activity to all of the cancer cells. Accordingly, thepossibility that Compound X possesses anti-cancer activity against humangastric cancer cell, human breast cancer cell, small cell lung cancer,pancreatic cancer cell, prostate cancer cell, kidney cancer cell,medulloblastoma, human sarcoma cell (rhabdomyosarcoma, Ewing's sarcomaand liposarcoma), and multiple myeloma, was strongly suggested.

Test Example 2 Evaluation of Cell Proliferation Inhibitory ActivityAgainst Human Leukemia Cell

Cell proliferation inhibitory effects against human leukemia cell withrespect to the compound described in Production Example 8 having PPARγactivating action (hereinafter referred to as Compound X) was studied byusing human leukemia cell lines HL-60 and THP-1 that were purchased fromAmerican Tissue Culture Collection. These cells were cultured using 10%fetal bovine serum (Hyclone Laboratories, Inc.)-RPMI (InvitrogenCorporation). HL-60 cells and THP-1 cells were inoculated on a 96-wellplate at 2×10³ cells/well, and at the same time, the agents at variousconcentrations dissolved in DMSO was added so that the concentration ofDMSO became 0.1%. The concentration of Compound X was studied at 10, 25and 50 μM (n=4). After the addition of the agent, cultivation wasconducted in the presence of 5% carbon dioxide at 37° C. for 5 days.Then, Cell Titer 96 Aqueous One Solution Reagent (Promega Corp.) wasadded at 40 μl/well each, followed by 2 hours of cultivation. AbsorbanceA490 of each well was measured using MICROPLATE READER Model 3550(Bio-Rad Laboratories, Inc.). The average absorbance of each of thegroups, which had been treated with respective concentrations ofCompound X, was presented as a percentage expression, by taking theaverage absorbance of the control group, which had been treated withDMSO, as 100%. Accordingly, the cancer cell proliferation inhibitoryactivity of Compound X was studied by subtracting this value from 100%.

The results are shown in Table 1.

TABLE 1 Concentration of HL-60 Proliferation THP-1 ProliferationCompound X [μM] inhibition rate % inhibition rate % 10 23  7 25 27* 20 50  45**  48** *P < 0.05, **P < 0.01 (against agent non-addition group,Students' t test)

From the results in Table 1, it was shown that Compound X significantlyinhibits proliferation activity of human leukemia cells.

Test Example 3 Evaluation of In Vivo Anti-Tumor Activity Against HumanColon Cancer Cells

In vivo anti-tumor activity against human colon cancer cells by thecompound described in Production Example 8 having PPARγ activatingaction (hereinafter referred to as Compound X) and the compounddescribed in Production Example 1 having PPARγ activating action(hereinafter referred to as Compound Y) was studied. In the experiment,human colon cancer line WiDr (purchased from American Type CultureCollection), in which it was confirmed that no mouse pathogenicmicroorganism was detected by quarantine, was transplanted to asubcutaneous axillary portion of a nude mouse BALB/cA Jcl-nu (CLEAJapan, Inc.), to subculture a tumor. The tumor was cut into small piecesof 5 mm size, and was transplanted to a right subcutaneous axillaryportion of a BALB/cA Jcl-nu mouse by using a troker (CLEA Japan, Inc.).The required amounts of Compounds X and Y were each weighed and weredissolved in N,N-dimethylacetamide (DMA: Wako Pure Chemical Industries,Ltd.), and 5% Emulphor 620 (GAF Corporation)-saline (OtsukaPharmaceutical Co., Ltd.) was then added to the mixtures in smallamounts, so that the concentrations of the compounds were each adjustedto 0.2, 1 or 5 mg/mL. Here, DMA was made to have a final concentrationof 2.5%. Each of these compound administration solutions wasadministered orally to a WiDr tumor-bearing nude mouse using a sonde(Fuchigami Kikaiten) from the day after transplantation of the tumor,once a day, 5 times per week, until 32 days after transplantation, inthe amount of 0.1 mL per 10 g of mouse weight. Twice a week, the majoraxis and the minor axis of the transplanted tumor were measured usingdigital micrometer calipers (MAX-CAL MAX-15: Nihon Sokutei KouguKabusiki Kaisha), and tumor proliferation inhibitory activity wasobtained from the following calculation formula and expressed as thetumor volume inhibition rate.

Average tumor volume in each test group (mm³)=½×(minor axis)²(mm²)×(major axis) (mm)

Tumor volume inhibition rate (%)={1−(average tumor volume of drugadministration group/average tumor volume of drug non-administrationgroup)}×100

Evaluation of anti-tumor activity of each of the drug administrationgroups was determined by the tumor volume inhibition rate. In addition,a statistical difference test was determined by conducting Students' ttest with respect to the tumor the volume of drug non-administrationcontrol group and the drug administration group 38 days aftertransplantation. Here, it was determined that there is a significantdifference between the two groups when the p value is less than 0.05.

The results are shown in Table 2.

TABLE 2 Administration Tumor volume inhibition rate (%)^(a)) Compoundamount [mg/kg] Exp. 1 Exp. 2 Compound X 50 49* 38* 10   N.D.^(b)) 35* 2N.D. 31* Compound Y 50 35* 40* 10 N.D. 32* 2 N.D. 26* ^(a))WiDr,determined on Day 35 ^(b))N.D.; not done *b < 0.01

From the results shown in Table 2, it became apparent that Compounds Xand Y both show significant in vivo anti-tumor activity against humancolon cancer line.

Test Example 4 Evaluation of In Vitro Cell Proliferation InhibitoryActivity Against Human Non-Small-Cell Lung Cancer Line by CombinationAdministration of a Compound having PPARγ Activating Action and anEpidermal Growth Factor Receptor (EGFR) Inhibitor

Effects of combined administration of the compound described inProduction Example 8 having PPARγ activating action (hereinafterreferred to as Compound X) and an epidermal growth factor receptor(EGFR) inhibitor against human non-small-cell lung cancer line A549 werestudied by using in vitro cell proliferation inhibitory activity as anindicator.

Human non-small-cell lung cancer line A549 cells (purchased fromAmerican Tissue Culture Collection) were cultured using 10% fetal bovineserum (Hyclone Laboratories, Inc.)-RPMI (Invitrogen Corporation). A549cells were inoculated on a 96-well plate at 5×10² cells/well, and at thesame time, the agents of various concentrations dissolved in DMSO wereadded so that the concentration of DMSO became 0.1%. Compound X wasstudied with a concentration of 10 μM, and gefitinib (synthesized bySankyo Company, Limited), as the EGFR inhibitor, with two concentrationsof 0.1 and 0.5 μM (n=4). After the addition of the drugs, cells werecultivated in the presence of 5% carbon dioxide at 37° C. for 7 days.Then, Cell Titer 96 Aqueous One Solution Reagent (Promega Corp.) wasadded at 40 μl/well each, followed by 2 hours of cultivation. AbsorbanceA490 of each well was measured using MICROPLATE READER (Bio-RadLaboratories, Inc.). The average absorbance of each of the groups, whichhad been treated with Compound X and gefitinib with respectiveconcentrations, was presented as a percentage expression, by taking theaverage absorbance of the compound non-added control group (treated withDMSO only), as 100%. Accordingly, the cancer cell proliferationinhibitory action of Compound X, gefitinib, and a combination of thesewere considered by subtracting this value from 100%.

The results are shown in Table 3.

TABLE 3 Compound concentration Compound X [μM] 0 0 0 10 10  10 Gefitinib [μM] 0 0.1 0.5 0   0.1   0.5 Cell proliferation 0 5 22 12 37*50* inhibition rate [%] *P < 0.05, (combined administration group versuseach of single-drug treated group, Students' t test)

As shown in Table 3, the single-drug treatment with Compound X (10 μM)showed a proliferation inhibition rate of 12%, and the single-drugtreatment with gefitinib (0.5 μM) showed a proliferation inhibition rateof 22%; however, the combined administration of both drugs showed aproliferation inhibition rate of 50%. From these results, it becameapparent that the combined administration of Compound X and theepidermal growth factor receptor (EGFR) inhibitor shows synergisticcancer cell proliferation inhibitory activity.

Test Example 5 Evaluation of In Vivo Anti-Tumor Activity AgainstNon-Small-Cell Lung Cancer

In vivo anti-tumor activity against non-small-cell lung cancer of thecompound described in Production Example 8 (hereinafter referred to asCompound X) was studied.

In the experiment, human non-small-cell lung cancer line A549 (purchasedfrom American Type Culture Collection), in which it was confirmed thatno mouse pathogenic microorganism was detected by quarantine, wastransplanted to a subcutaneous axillary portion of a nude mouse BALB/cAJcl-nu (CLEA Japan, Inc.), to subculture a tumor. The tumor was cut intosmall pieces of 5 mm size, and transplanted to a right subcutaneousaxillary portion of a BALB/cA Jcl-nu mouse by using a troker (CLEAJapan, Inc.). Required amounts of Compound X and gefitinib (synthesizedby Sankyo Company, Limited) as the EGFR inhibitor were each weighed, andsolutions were prepared by suspending the compound described inProduction Example 8 which has PPARγ activating action (hereinafterreferred to as Compound X) in a 0.5%-methyl cellulose solution to have afinal concentration of 1 mg/mL, and gefitinib in 0.05% Tween 80 (TokyoChemical Industry Co., Ltd.) to have a final concentration of 10 mg/mL.Each of these compound administration solutions was administered orallyto a A549 tumor-bearing nude mouse using a sonde (Fuchigami Kikaiten)from 14 days after transplantation of the tumor, once a day, 5 times perweek, until 60 days after transplantation, in the amount of 0.1 mL per10 g of mouse weight. Twice a week, the major axis and the minor axis ofthe transplanted tumor were measured using digital micrometer calipers(MAX-CAL MAX-15: Nihon Sokutei Kougu Kabusiki Kaisha), and tumorproliferation inhibitory activity was obtained from the followingcalculation formula and expressed as the tumor volume inhibition rate.

The average tumor volume in each test group (mm³)=½×(minor axis)²(mm²)×(major axis) (mm)

Tumor volume inhibition rate (%)={1−(average tumor volume of drugadministration group/average tumor volume of drug non-administrationgroup)}×100

Evaluation of anti-tumor activity for each of the drug administrationgroups was determined by the tumor volume inhibition rate. In addition,a statistical difference test was determined by conducting Students' ttest with respect to tumor volume of the drug non-administration controlgroup and the drug administration group 63 days after transplantation.Here, it was determined that there is a significant difference betweenthe two groups when the p value is less than 0.05.

The results are shown in FIG. 4.

As shown in FIG. 4, Compound X showed significant anti-tumor activity bya tumor volume inhibition rate of 33%. In addition, gefitinib alsoshowed significant anti-tumor activity by a tumor volume inhibition rateof 56%. On the other hand, when Compound X and gefitinib wereadministered in combination, enhancement in anti-tumor activity with asignificant difference compared with that of the Compound X single-drugadministration group and with that of the gefitinib single-drugadministration group, was observed by a tumor volume inhibition rate of73%. From these results, it became apparent that Compound X hasanti-tumor activity against human non-small-cell lung cancer and thatanti-tumor activity can be enhanced by its combined administration withan epidermal growth factor receptor (EGFR) inhibitor.

Test Example 6 Evaluation of In Vitro Cell Proliferation InhibitoryActivity Against Human Non-Small-Cell Lung Cancer Line by CombinedAdministration of a Compound having PPARγ Activating Action with anInhibitor of Vascular Endothelial Growth Factor Receptor (VEGFR) and RafKinase

Effects of the combined administration of the compound described inProduction Example 8 having PPARγ activating action (hereinafterreferred to as Compound X), and a vascular endothelial growth factorreceptor (VEGFR) and Raf kinase inhibitor, against human non-small-celllung cancer line was studied by using cell proliferation inhibitoryactivity as an indicator.

Human non-small-cell lung cancer line A549 cells were inoculated on a96-well plate at 5×10² cells/well, and at the same time, agents ofvarious concentrations dissolved in DMSO were added so that theconcentration of DMSO became 0.1%. Compound X was studied with aconcentration of 10 μM, and for sorafenib (synthesized by SankyoCompany, Limited), which has VEGFR inhibitory activity and Raf kinaseinhibitory activity, with a concentration of 5 μM (n=4). After additionof the drugs, the cells were cultivated in the presence of 5% carbondioxide at 37° C. for 6 days. Then, Cell Titer 96 Aqueous One SolutionReagent (Promega Corp.) was added at 40 μl/well each, and thenabsorbance A490 of each well was measured using MICROPLATE READER(Bio-Rad Laboratories, Inc.). The average absorbance of each of thegroups, which had been treated with respective concentrations ofCompound X and sorafenib, was presented as a percentage expression, bytaking the average absorbance of the compound non-addition control group(treated with DMSO only), as 100%. Accordingly, the cancer cellproliferation inhibitory activity of Compound X, sorafenib, and thecombination of these were studied by subtracting this value from 100%.

The results are shown in Table 4.

TABLE 4 Proliferation inhibition rate [%] Compound X 15 Sorafenib 47Compound X and sorafenib  71** **P < 0.01, (combined administrationgroup versus each of single-drug treated group, Students' t test)

As shown in Table 4, the single-drug treatment with Compound X (10 μM)showed a proliferation inhibition rate of 15%, and the single-drugtreatment with sorafenib (5 μM) showed a proliferation inhibition rateof 47%; however, the combined administration of both drugs showed aproliferation inhibition rate of 71%. Here, the proliferation inhibitionactivity in the combined administration group showed a statisticaldifference, when compared with each of the single-drug treated groups.From these results, it became apparent that the combined administrationof Compound X, and the vascular endothelial growth factor receptor(VEGFR) and Raf kinase inhibitor shows synergistic cancer cellproliferation inhibitory activity.

Test Example 7 Evaluation of In Vivo Anti-tumor Activity Against HumanKidney Cancer by the Combined Administration of a Compound Having PPARγActivating Action with an Inhibitor of Vascular Endothelial GrowthFactor Receptor (VEGFR) and Raf Kinase

In vivo anti-tumor activity against human kidney cancer of the compounddescribed in Production Example 8 having PPARγ activating action(hereinafter referred to as Compound X) was studied.

In the experiment, human non-small-cell lung cancer line SN12-PM6(provided by Professor Seiji Naito of Kyushu University), in which itwas confirmed that no mouse pathogenic microorganism was detected byquarantine, was transplanted to a subcutaneous axillary portion of anude mouse BALB/cA Jcl-nu (CLEA Japan, Inc.), to subculture a tumor. Thetumor was cut into small pieces in a size of 5 mm, and transplanted to aright subcutaneous axillary portion of a BALB/cA Jcl-nu mouse by using atroker (CLEA Japan, Inc.). The required amounts of Compound X andsorafenib (synthesized by Sankyo Company, Limited), which has VEGFRinhibitory action and Raf kinase inhibitory action, were each weighed,and solutions were prepared by suspending Compound X in a 0.5%-methylcellulose solution, and sorafenib in 50% ethanol (Kanto Chemical Co.,Inc.)-50% cremophor (Sigma). Subsequently, distilled water (OtsukaPharmaceutical Factory, Inc.) was added so that the final concentrationsof ethanol and cremophor became each 12.5%. The solutions were preparedso that the final concentrations of Compound X and sorafenib became 0.3mg/mL and 10 mg/mL respectively. Each of these compound administrationsolutions was administered orally to a SN12-PM6 tumor-bearing nude mouseusing a sonde (Fuchigami Kikaiten) from 10 days after thetransplantation of the tumor, once a day, 5 times per week, until 56days after transplantation, in the amount of 0.1 mL per 10 g of mouseweight. Twice a week, the major axis and the minor axis of thetransplanted tumor were measured using digital micrometer calipers(MAX-CAL MAX-15: Nihon Sokutei Kougu Kabusikikaisha), and tumorproliferation inhibitory activity was obtained from the followingcalculation formula and expressed as the tumor volume inhibition rate.

Average tumor volume in each test group (mm²)=½×(minor axis)²(mm²)×(major axis)(mm)

Tumor volume inhibition rate (%)={1−(average tumor volume of drugadministration group/average tumor volume of drug non-administrationgroup)}×100

Evaluation of anti-tumor activity for each of the drug administrationgroup was determined by the tumor volume inhibition rate. In addition, astatistical difference test was determined by conducting Students' ttest with respect to the tumor volumes of the drug non-administrationcontrol group and the drug administration group 59 days aftertransplantation. Here, it was determined that there is a significantdifference between the two groups when p value is less than 0.05.

The results are shown in FIG. 5.

As shown in FIG. 5, Compound X significantly inhibited proliferation ofhuman kidney cancer line SN12-PM6 by single-drug administration (tumorvolume inhibition rate of 37%). In addition, single-drug administrationof sorafenib also showed significant proliferation inhibitory activity(tumor volume inhibition rate of 43%). On the other hand, when CompoundX and sorafenib were administered in combination, enhancement inanti-tumor activity with a significant difference compared with that ofthe Compound X single-drug administration group and with that of thesorafenib single-drug administration group was observed by a tumorvolume inhibition rate of 65%. From these results, it became apparentthat Compound X has anti-tumor activity against human kidney cancer andthat anti-tumor activity can be enhanced by its combined administrationwith a vascular endothelial growth factor receptor (VEGFR) and Rafkinase inhibitor.

BRIEF DESCRIPTION OF THE DRAWINGS

[FIG. 1] This is a graph showing the relationship between theconcentration of Compound X and cancer cell proliferation inhibitoryactivity, in which plotting is made by taking the absorbance (%) of eachof the cells after addition of Compound X to each of the cancer cells asthe longitudinal axis, and the concentration (μM) of Compound X added asthe horizontal axis.

[FIG. 2] This is a graph showing the relationship between theconcentration of Compound X and cancer cell proliferation inhibitoryactivity, in which plotting is made by taking the absorbance (%) of eachof the cells after addition of Compound X to each of the cancer cells asthe longitudinal axis, and the concentration (μM) of Compound X added asthe horizontal axis.

[FIG. 3] This is a graph showing the relationship between theconcentration of Compound X and cancer cell proliferation inhibitoryactivity, in which plotting is made by taking the absorbance (%) of eachof the cells after addition of Compound X to each of the cancer cells asthe longitudinal axis, and the concentration (μM) of Compound X added asthe horizontal axis.

[FIG. 4] This is a graph showing the relationship between days aftertransplantation and tumor volume, in which plotting is made by takingthe tumor volume (mm³), for the cases where Compound X alone, gefitinibalone, or the combination of both drugs was used for the transplantedcancer cells, as the longitudinal axis, and the days aftertransplantation (day) as the horizontal axis.

[FIG. 5] This is a graph showing the relationship between days aftertransplantation and tumor volume, in which plotting is made by takingthe tumor volume (mm³), for the cases where Compound X alone, sorafenibalone, or the combination of both drugs was used for transplanted cancercells, as the longitudinal axis, and the days after transplantation(day) as the horizontal axis.

1. An anti-cancer pharmaceutical composition for treatment of carcinoma,sarcoma or hematopoietic cancer comprising: (a) an effective amount ofat least one anti-cancer drug selected from the group consisting of anepidermal growth factor receptor (EGFR) inhibitor, a vascularendothelial growth factor receptor (VEGFR) inhibitor and a Raf kinaseinhibitor and (b) an effective amount of5-(4-(6-(4-amino-3,5-dimethyl-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochlorideas active ingredients provided that said carcinoma is not lung cancerwhen an EGFR inhibitor is erlotinib.
 2. The pharmaceutical compositionof claim 1, wherein said anti-cancer drug (a) is at least one selectedfrom the group consisting of cetuximab, panitumumab, erlotinib,lapatinib, bevacizumab, SU11248 and vatalanib.
 3. The pharmaceuticalcomposition of claim 1, wherein said anti-cancer drug (a) is at leastone selected from the group consisting of gefitinib and sorafenib. 4.The pharmaceutical composition of claim 1, wherein said composition isfor the treatment of breast cancer, pancreatic cancer, kidney cancer orprostate cancer.
 5. The pharmaceutical composition of claim 1, whereinsaid composition is for the treatment of medulloblastoma,rhabdomyosarcoma, Ewing sarcoma or liposarcoma.
 6. The pharmaceuticalcomposition of claim 1, wherein said composition is for the treatment ofliposarcoma.
 7. The pharmaceutical composition of claim 1, wherein saidcomposition is for the treatment of multiple myeloma or leukemia.
 8. Amethod of treating a person having a cancer selected from carcinoma,sarcoma or hematopoietic cancer comprising administering: (a) aneffective amount of at least one anti-cancer drug selected from thegroup consisting of an epidermal growth factor receptor (EGFR)inhibitor, a vascular endothelial growth factor receptor (VEGFR)inhibitor and a Raf kinase inhibitor and (b) an effective amount of5-(4-(6-(4-amino-3,5-dimethyl-phenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy)-benzyl)-thiazolidine-2,4-dione.dihydrochlorideprovided that said carcinoma is not lung cancer when an EGFR inhibitoris erlotinib.
 9. The method of claim 8, wherein said anti-cancer drug(a) is at least one selected from the group consisting of panitumumab,lapatinib, bevacizumab, SU11248 and vatalanib.
 10. The method of claim8, wherein said anti-cancer drug (a) is at least one selected from thegroup consisting of cetuximab, gefitinib, erlotinib and sorafenib. 11.The method of claim 8, wherein said method is for the treatment of lungcancer, and said anti-cancer drug (a) is gefitinib.
 12. The method ofclaim 8, wherein said method is for the treatment of kidney cancer, andsaid anti-cancer drug (a) is sorafenib.
 13. The method of claim 8,wherein said carcinoma is for the treatment of kidney cancer, and saidanti-cancer drug (a) is sorafenib.
 14. The method of claim 8, whereinsaid cancer is medulloblastoma, rhabdomyosarcoma, Ewing sarcoma orliposarcoma.
 15. The method of claim 8, wherein said cancer is multiplemyeloma or leukemia.
 16. The method of claim 8, wherein said cancer isliposarcoma.